bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2025–07–06
fifty-nine papers selected by
Lakesh Kumar, BITS Pilani
  1. Surface antigen SAG1 mediates Toxoplasma gondii fitness and host cell attachment in IFNγ-stimulated cells.
  2. A sialic acid-binding protein in Toxoplasma gondii contains a conserved globular domain in apicomplexan parasites.
  3. Deciphering cell cycle organization of Toxoplasma endodyogeny.
  4. ATF3-mediated inhibition of Trem2 by Toxoplasma gondii contributes to adverse pregnancy outcomes.
  5. RNA triphosphatase-mediated mRNA capping is essential for maintaining transcript homeostasis and the survival of Toxoplasma gondii.
  6. Regulation of the developmental programs in Toxoplasma by a novel SNF2L-containing chromatin remodeling complex.
  7. A P5-ATPase, TgFLP12, diverging from plant chloroplast lipid transporters mediates apicoplast fatty export in Toxoplasma.
  8. Computational Structural Comparison of Toxoplasma gondii CDPK1 and Human BUB1 kinases: Implications for Selective Inhibitor Design.
  9. Interferons and Toxoplasma gondii shape PD-L1 regulation in retinal barrier cells: the critical role of proteases.
  10. Histone and Non-histone Reversible Acetylation in Development, Aging, and Disease.
  11. Development of novel benzamide class I selective lysine deacetylase inhibitors as potent anticancer agents.
  12. Acetylation and Deacetylation of Cytoskeleton-Associated Proteins.
  13. Enteroepithelial stages of Toxoplasma gondii in the ileum of cats by serial block face scanning electron microscopy.
  14. Reversible Acetylation of Non-histone Proteins in Human Cancers.
  15. Epigenetic Echoes: Decoding the Acetylation Journey from Neural Crest to Melanocyte.
  16. Toxoplasma gondii infection risk among pregnant people and congenital toxoplasmosis incidence in Japan.
  17. The role of HDAC6 in fibrosis: a novel and effective therapy strategy.
  18. Impact of Histone Acetyltransferases and Histone Deacetylases on Adult Brain Myelin Plasticity.
  19. Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages.
  20. Hydroxamic acid hybrids as histone deacetylase inhibitors for cancer therapy: an update (2022 to date).
  21. Characterization of the malaria parasite Plasmodium falciparum Tepsin homolog.
  22. Presumed bilateral endogenous Cryptococcus neoformans endophthalmitis with concomitant Toxoplasma gondii retinochoroiditis.
  23. Tubulin Acetylation: A Critical Regulator of Microtubule Function.
  24. Targeting negative phosphorylation to activate AMPK.
  25. Lysine Acetyltransferase 6 Complexes in Neurodevelopmental Disorders and Different Types of Cancer.
  26. Muscle needs NAD, but how much?
  27. Acetylation in Viral Infection and Disease.
  28. Palmitic Acid Induces Dynamic Time-Dependent Alterations in HDACs, Neuronal Chromatin Acetylation, and Gene Expression.
  29. High-Throughput Post-Translational Modification Analyses by Reverse Phase Protein Array.
  30. Bromodomain and PHD Finger-Containing Protein 1: From Functions to a Developmental Disorder, Cancer, and Therapeutics.
  31. SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.
  32. Acetylation in Cardiac Aging: Molecular Mechanism and Therapeutic Approaches.
  33. Tubulin Acetylation and the Cellular Mechanosensing and Stress Response.
  34. Histone deacetylase 6 inhibitors in Alzheimer's disease therapy: structure design and challenges.
  35. Detection of Toxoplasma gondii and High-Risk Human Papillomaviruses in FFPE Malignant and Benign Breast Lesions Using Real-Time PCR.
  36. Knocking out histidine ammonia-lyase by using CRISPR-Cas9 abolishes histidine role in the bioenergetics and the life cycle of Trypanosoma cruzi.
  37. Histone lactylation as a driver of metabolic reprogramming and immune evasion.
  38. SIRT1 as a masterful reciprocal regulator of molecular mechanisms and signaling pathways involved in tumor growth and expansion.
  39. Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
  40. FGA, a new target of histone acetylation, inhibits apoptosis of granulosa cells in follicles.
  41. Complex interactions in the life cycle of a simple parasite shape the evolution of virulence.
  42. A paternal lactate dehydrogenase critically enhances male gametogenesis and malaria transmission.
  43. Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.
  44. Inhibitory Effect of Novel Dihydroxamate Derivatives for Histone Deacetylase 1.
  45. Metabolomic analysis of the impact of MtrA on carbon metabolism in Streptomyces coelicolor.
  46. Epigenetic regulators in cancer therapy and progression.
  47. Lack of knowledge of stakeholders in the pork value chain: Considerations for transmission and control of Taenia solium and Toxoplasma gondii in Burundi.
  48. Regulation of neuronal ankyrin localization and function by post-translational modifications.
  49. Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction.
  50. Targeting glutamine metabolism as a potential target for cancer treatment.
  51. Leishmania mexicana pathogenicity requires flagellar assembly but not motility.
  52. BAHCC1 binds H4K20me1 to facilitate the MCM complex loading and DNA replication.
  53. Functional characterisation of components in two Plasmodium falciparum Cullin-RING-Ligase complexes.
  54. Early dynamics of Toxoplasma gondii infection in sheep inoculated at mid-gestation with archetypal type II oocysts.
  55. The adhesion plaque mediates fluid discharge and duplication of the contractile vacuole complex in Trypanosoma cruzi.
  56. Lipidomics in Breast Cancer: Decoding Metabolic Reprogramming and Unlocking Therapeutic Opportunities.
  57. Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development.
  58. KMT2C and KMT2D regulate skeletal development through stage-specific epigenetic control of chondrogenesis.
  59. MLN0905 effectively kills gemcitabine-resistant pancreatic cancer cells by targeting PLK1.
  1. Infect Immun. 2025 Jul 03. e0001025
    Surface antigen SAG1 mediates Toxoplasma gondii fitness and host cell attachment in IFNγ-stimulated cells.
    Olivia Cohen, Parag Maru, Qinli Liang, Jeroen P J Saeij.
      Toxoplasma gondii is an obligate intracellular protozoan parasite that can establish lifelong infections and cause severe disease in immunocompromised individuals. Interferon gamma (IFNγ) is a key host defense cytokine that induces a variety of toxoplasmacidal mechanisms. Recent CRISPR/Cas9 loss-of-function screens identified multiple Toxoplasma genes important for fitness in IFNγ-stimulated cells. One consistent hit in several screens was the parasite surface antigen, SAG1. Here, we used CRISPR/Cas9 to generate a SAG1 knockout strain and found that SAG1 is important for parasite fitness specifically in IFNγ-stimulated cells. Mechanistic studies revealed that host surface sialic acids are important for parasite attachment, especially in IFNγ-stimulated cells. SAG1-deficient parasites had reduced attachment efficiency, which was exacerbated in IFNγ-treated cells. These findings highlight the role of SAG1 in mediating robust parasite attachment, especially in the context of immune pressure.
    Keywords:  SAG1; Toxoplasma; attachment; interferon gamma; sialic acid; surface antigen
    DOI:  https://doi.org/10.1128/iai.00010-25
  2. Parasit Vectors. 2025 Jul 01. 18(1): 239
    A sialic acid-binding protein in Toxoplasma gondii contains a conserved globular domain in apicomplexan parasites.
    Xiaoyu Sang, Yize Liu, Yiwei Zhang, Ran Chen, Ying Feng, Ning Jiang, Qijun Chen.
       BACKGROUND: Apicomplexan protozoans employ an intricate invasion mechanism involving dynamic interactions with host cells, characterized by sequential secretion of adhesins and lectins. Our laboratory previously identified TgSABP1, a novel Toxoplasma gondii adhesin, demonstrating specific binding affinity for sialic acid (SA) receptors on host cell surfaces. However, the structural determinants governing SA recognition by this adhesin remain undefined.
    METHODS: Three-dimensional structural predictions of TgSABP1 and homologous proteins were generated using AlphaFold2. Bio-layer interferometry (BLI) quantified the binding affinities between the recombinant proteins and ligands. Competitive BLI assays evaluated small molecules that potentially inhibit the TgSABP1-sialyllactose interactions. Molecular docking simulations employing AutoDock Vina software elucidated ligand-binding site interactions. In vitro invasion inhibition assays were performed to assess the therapeutic potential of lead compounds targeting TgSABP1 against T. gondii tachyzoites.
    RESULTS: AlphaFold2 structural predictions revealed that TgSABP1 and its homologues contain a conserved globular domain (pLDDT > 90) with significant structural homology (with root-mean-square deviation [RMSD] < 4 Å) to a Plasmodium falciparum invasion-related protein PfIMP2 (PDB: 5LG9). BLI quantification demonstrated the micromolar binding affinities of the recombinant proteins for 3'-sialyllactose-polyacrylamide (PAA) and 6'-sialyllactose (6'SL)-PAA. Intriguingly, although recombinant TgSABP1 showed stronger lactose binding (KD = 0.02 ± 0.01 M) compared to SA (KD = 2.07 ± 0.45 M), only the latter exhibited an inhibition on the TgSABP1-6'SL-PAA interaction. Virtual screening of Food and Drug Administration (FDA)-approved compounds identified eltrombopag as a high-affinity molecule (ΔGbind = -8.3 kcal/mol) targeting the SA-binding pocket in TgSABP1. Functional validation demonstrated that eltrombopag effectively blocked the TgSABP1/6'SL-PAA interaction and significantly decreased host cell invasion of T. gondii tachyzoites.
    CONCLUSIONS: Our study reveals a conserved globular domain of apicomplexan parasites as a novel SA-binding domain. Structural and functional characterization demonstrates its critical role in mediating TgSABP1-host cell interactions. Targeting this SA-binding pocket with eltrombopag effectively decreased T. gondii tachyzoite invasion, suggesting its therapeutic potential as an anti-invasion target. These findings not only elucidate a conserved mechanism underlying host receptor recognition in apicomplexans, but also establish a structural framework for the rational design of broad-spectrum inhibitors targeting invasion-related lectin domains.
    Keywords:   Toxoplasma gondii ; Globular domain; Sialic acid
    DOI:  https://doi.org/10.1186/s13071-025-06845-5
  3. mBio. 2025 Jul 01. e0111925
    Deciphering cell cycle organization of Toxoplasma endodyogeny.
    Mrinalini Batra, Clem Marsilia, Danya Awshah, Lauren M Hawkins, Chengqi Wang, Dale Chaput, Daria A Naumova, Elena S Suvorova.
      In this study, we report the atypical cell cycle organization of the unicellular eukaryotic pathogen Toxoplasma gondii. The remarkably flexible cell division of T. gondii and other apicomplexan parasites differs considerably from the cell division modes employed by other model eukaryotes. In addition, there is a lack of recognizable cell cycle regulators, which has contributed to the difficulties in deciphering the order of events in the apicomplexan cell cycle. To aid in studies of the cell cycle organization of the T. gondii tachyzoite, we have created the Fluorescent Ubiquitination-based Cell Cycle Indicator probes, ToxoFUCCIS and ToxoFUCCISC. We introduced a DNA replication factor TgPCNA1 tagged with NeonGreen that can be used alone or in conjunction with an mCherry-tagged budding indicator TgIMC3 in the auxin-induced degradation parental strain. The varied localization and dynamic cell cycle oscillation have confirmed TgPCNA1 to be a suitable T. gondii FUCCI probe. The ToxoFUCCIS analysis showed that tachyzoite DNA replication starts at or near centromeric regions and has a bell-shaped dynamic and a significant degree of the cell cycle asynchrony within the vacuoles. Quantitative live and immunofluorescence microscopy analyses of ToxoFUCCIS and its derivatives co-expressing epitope-tagged cell cycle markers have revealed an unusual composite cell cycle phase that incorporates overlapping S, G2, mitosis, and cytokinesis (budding). We identified five intervals of the composite phase and their approximate duration: S (19%), S/G2/C (3%), S/M/C (9%), M/C (18%), and C/G1 (<1%). The ToxoFUCCIS probe efficiently detected G2/M and Spindle Assembly Checkpoints, as well as the SB505124-induced TgMAPK1-dependent block. Altogether, our findings showed an unprecedented complexity of the cell cycle in apicomplexan parasites.
    IMPORTANCE: The cell division rates directly correlate with the severity of the diseases caused by apicomplexan parasites. Despite its clinical importance, little is known about the apicomplexan cell cycle that controls parasite division rates. Previous studies implied that the apicomplexan cell cycle is organized differently from the cell cycle of their host cells. However, the order of cell cycle events had never been established. In the current study, we present evidence of the highly unusual organization of the Toxoplasma gondii cell cycle. Using a new cell cycle indicator, we measured the duration of individual cell cycle processes in Toxoplasma tachyzoites and revealed the unprecedented overlaps of four cell cycle phases. Our findings explain how the apicomplexan cell cycle accommodates the flexibility of the division modes and identify unique steps of the parasite survival program that can be explored in the future.
    Keywords:  Apicomplexa; Cdk-related kinase; FUCCI; PCNA1; Toxoplasma gondii; cell cycle
    DOI:  https://doi.org/10.1128/mbio.01119-25
  4. Parasit Vectors. 2025 Jul 01. 18(1): 245
    ATF3-mediated inhibition of Trem2 by Toxoplasma gondii contributes to adverse pregnancy outcomes.
    Xiaoyu Geng, Tiankun Yao, Xinyue Wang, Jianan Wang, Tongrui Zhang, Tianmei Qian, Chun Liu, Jinling Chen.
       BACKGROUND: Approximately one in three people worldwide have been exposed to Toxoplasma gondii (T. gondii). Primary infection with T. gondii during pregnancy can cause severe complications. Our previous study demonstrated that deficiency of triggering receptor expressed on myeloid cells 2 (Trem2) exacerbates pregnancy-related complications in T. gondii-infected mice. However, understanding the mechanisms by which T. gondii modulates Trem2 expression in macrophages remains an unmet challenge.
    METHODS: A mouse pregnancy model of T. gondii infection and an in vitro cellular stimulation model using soluble T. gondii antigens (sTgAg) were used to assess Trem2 expression. Recombinant plasmids containing the full-length Trem2 promoter were constructed to evaluate the effect of sTgAg on promoter activity, followed by the construction of truncated promoter plasmids to identify key regulatory regions. Transcription factors potentially binding to the Trem2 promoter were predicted using PROMO and JASPAR, with ATF3 identified as responsive to sTgAg stimulation via western blot analysis. The binding of ATF3 to the Trem2 promoter was validated by chromatin immunoprecipitation (ChIP) assays. Finally, ATF3 knockdown experiments were performed to determine its role in mediating the inhibitory effect of sTgAg on Trem2 expression.
    RESULTS: T. gondii significantly suppressed Trem2 expression in both mouse placentas and cellular models, with truncated promoter assays identifying key regulatory regions of the Trem2 promoter inhibited by sTgAg. ATF3 was identified as a transcription factor responsive to sTgAg stimulation, which bound to the Trem2 promoter. Importantly, knockdown of ATF3 restored Trem2 expression, demonstrating its critical role in mediating the inhibitory effect of sTgAg.
    CONCLUSIONS: We identified that sTgAg may target and inhibit Trem2 expression through the transcription factor ATF3, and inhibition of ATF3 activity may help maintain Trem2 expression in macrophages, providing a potential therapeutic approach to avert negative effects on pregnancy related to T. gondii infection.
    Keywords:   ATF3 ; Toxoplasma gondii ; Trem2 promoter; Adverse pregnancy outcomes; Macrophages
    DOI:  https://doi.org/10.1186/s13071-025-06894-w
  5. Nat Commun. 2025 Jul 01. 16(1): 5452
    RNA triphosphatase-mediated mRNA capping is essential for maintaining transcript homeostasis and the survival of Toxoplasma gondii.
    Kalyani R Aswale, Poonam Kashyap, Abhijit S Deshmukh.
      RNA modifications are crucial for gene expression in eukaryotes; however, the regulatory role of 5' 7-methylguanosine (m7G) cap, the first modification of mRNA, remains unknown in the protozoan parasite Toxoplasma gondii. Here, we show that the mRNA capping machinery of Toxoplasma consists of three distinct enzymes: RNA triphosphatase, guanylyltransferase, and guanine-N7-methyltransferase, which together add m7G cap to RNA, recognized by cap-binding protein, TgeIF4E. Biochemical and genetic studies show that among three capping enzymes, RNA triphosphatase (TgCet) is unique and a member of the tunnel family of metal-dependent phosphohydrolases, which is structurally and mechanistically distinct from the human RNA triphosphatase. Using conditional knockdown, we show that TgCet is essential for mRNA capping, and its depletion generates widespread changes in m7G-capped transcripts, resulting in the complete arrest of parasite replication both in culture and in mouse host, thereby protecting them from lethal infection. Finally, the therapeutic potential of TgCet was evaluated using two compounds, Myricetin and 3,4-dicaffeoylquinic acid, reported to inhibit Trypanosoma Cet enzyme. However, only Myricetin demonstrated selective inhibition of TgCet activity and effectively blocked parasite growth in culture. Overall, this study highlights the essential role of TgCet-mediated mRNA capping, establishing RNA triphosphatase as a promising drug target for Toxoplasma infection.
    DOI:  https://doi.org/10.1038/s41467-025-59867-z
  6. Nat Commun. 2025 Jul 01. 16(1): 5757
    Regulation of the developmental programs in Toxoplasma by a novel SNF2L-containing chromatin remodeling complex.
    Yuchao Zhu, Bolin Fan, Hao Xu, Yazhou Li, Xiaohan Liang, Lilan Xue, Liting Wei, Fuqiang Fan, Xin Zhang, Yukun Chen, Shanshan Qian, Bang Shen.
      Toxoplasma gondii is an extremely successful parasite infecting one third of the human population and numerous animals. It has a complex life cycle with multiple developmental stages that are key for its transmission and pathogenesis. But how the developmental programs are regulated is largely unknown. Here, we screen putative chromatin remodeling proteins in T. gondii and find that a novel complex containing an evolutionarily conserved ATPase SNF2L is critical for programming the parasite's development. This complex contains four core proteins and conditional depletion of three of them leads to similar expression changes of developmentally regulated genes, including increased transcription of genes involved in sexual commitment and development. Accordingly, depletion of SNF2L causes merogony and out-budding types of division, which are otherwise only observed at the enteroepithelial stages within definitive hosts where sexual reproduction of the parasite occurs. After being recruited to target regions, SNF2L regulates gene expression by modulating local chromatin accessibility or by recruiting accessory proteins to its binding sites, thus ensuring that the gene expression and reproduction patterns are matched to the life cycle stages. Conditional depletion of SNF2L offers an opportunity to study the unique biology of the parasite during pre-sexual and sexual developments in vitro.
    DOI:  https://doi.org/10.1038/s41467-025-60795-1
  7. Nat Commun. 2025 Jul 01. 16(1): 5538
    A P5-ATPase, TgFLP12, diverging from plant chloroplast lipid transporters mediates apicoplast fatty export in Toxoplasma.
    Christophe-Sébastien Arnold, Anna-Maria Alazzi, Serena Shunmugam, Jan Janouškovec, Laurence Berry, Sarah Charital, Thierry Gautier, Samuel Duley, Delphine Jublot, Catherine Lemaire-Vieille, Marie-France Cesbron-Delauw, Pierre Cavailles, Jérôme Govin, Nicholas J Katris, Yoshiki Yamaryo-Botté, Cyrille Y Botté.
      Toxoplasma gondii, an apicomplexan parasite and agent of the human disease toxoplasmosis, possesses a non-photosynthetic relic plastid, named the apicoplast. Thought to be evolved from a red algal plastid, the apicoplast houses major metabolic pathways, such as heme, isoprenoid and lipid synthesis, crucial for parasite survival, and thus considered attractive drug targets. However, despite similarities with plant chloroplast lipid synthesis pathways, the apicoplast lacks canonical plant/chloroplast lipid transporters and so metabolite import/export is at present, poorly characterised. Here we identify TgFLP12, a newly identified P5-ATPase transporter localised to the Toxoplasma apicoplast. TgFLP12 is found in the SAR (Stramenopile-Alveolata-Rhizaria) supergroup (to which belong Apicomplexa parasites and chromerids) but absent in higher plants. Disruption of TgFLP12 causes major defects on apicoplast morphology. Lipidomic analyses and stable isotope labelling reveal a unique accumulation of C14:0 in the apicoplast, which is then lacking in most major lipid classes subsequently synthesized in the ER. Successful complementation of a yeast mutant deficient in fatty acid transport with TgFLP12 validates TgFLP12 as a fatty acid transporter. Overall, we identify a potentially important drug target: the apicoplast fatty acid exporter, specific to Apicomplexa which unexpectedly also highlights Toxoplasma's utility as a model organism for investigating algal biology.
    DOI:  https://doi.org/10.1038/s41467-025-61155-9
  8. ACS Omega. 2025 Jun 24. 10(24): 25415-25431
    Computational Structural Comparison of Toxoplasma gondii CDPK1 and Human BUB1 kinases: Implications for Selective Inhibitor Design.
    João Pedro Bezerra Carvalho, Deborah Antunes, Daniel Adesse, Ana Carolina Guimarães.
      Toxoplasmosis, affecting one-third of the global human population, urgently requires new therapeutic strategies due to current treatment limitations and drug resistance. Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is a promising drug target due to its essential role in parasite survival and its presumed unique glycine gatekeeper residue. Aiming at identifying new and selective inhibitors of TgCDPK1, we performed computational structural analyses and unexpectedly found that a human kinase (BUB1), despite having only 14% sequence identity, shares this glycine gatekeeper with TgCDPK1, which initially raised concerns for selective inhibitor development. Subsequent analyses revealed distinct electrostatic properties and binding site architectures between these kinases. Molecular dynamics simulations demonstrate differential binding pocket dynamics, with TgCDPK1 showing more focused interaction networks compared to BUB1's dispersed patterns. Virtual screening of apicomplexan kinase inhibitors confirms stronger binding affinity for TgCDPK1 over BUB1, supporting the continued development of selective therapeutics against toxoplasmosis.
    DOI:  https://doi.org/10.1021/acsomega.5c00640
  9. Front Immunol. 2025 ;16 1607247
    Interferons and Toxoplasma gondii shape PD-L1 regulation in retinal barrier cells: the critical role of proteases.
    Benjamin Geiller, Camila Cevallos, Iuliia Tsybenko, Lydia Arnoux, Marie-Paule Felder-Schmittbuhl, Alexander W Pfaff.
       Introduction: The apicomplexan parasite Toxoplasma gondii establishes chronic infection in the central nervous system, including the retina, causing ocular toxoplasmosis (OT). This persistence relies on a fine balance between inflammatory and immunomodulatory mechanisms, especially in the immune-privileged ocular environment. We previously described the immunologic interactions between retinal cells, and particularly the roles of type I and III interferons. In this study, we investigated the regulatory dynamics of PD-L1, a central immunomodulatory receptor on immune cells.
    Methods: We first investigated the mechanisms of PD-L1 regulation and the roles of type I and III interferons in an in vitro T. gondii infection model using mono- and co-culture systems of human microglia, astrocytes, and Müller cells. We also assessed PD-L1 expression in an outer blood-retina barrier model (oBRB) of differentiated retinal pigmented epithelial (RPE) cells. Additionally, we looked at retinal cell activation, PD-L1 expression and the roles of these interferons in a mouse model of OT.
    Results: Our findings reveal new roles for type I and III interferons in regulating glial cell activation and PD-L1 expression in RPE, Müller, astrocytes and microglial cells. Notably, Müller cells, the most abundant glial cells in the retina, showed the highest baseline PD-L1 expression at both the mRNA and protein levels, and responded robustly to interferon stimulation. This points to a more prominent immunoregulatory role for Müller cells in the retina than previously recognized. Furthermore, we identified a parasite protease-dependent mechanism that reduces PD-L1 expression in our in vitro oBRB model potentially contributing to immune evasion and inflammation during OT. Finally, in a murine model of OT, we demonstrated that PD-L1 expression reached its peak on day 7 post-infection and that interferon neutralization plays a crucial role in regulating both PD-L1 expression and glial activation.
    Discussion: The parasite T. gondii orchestrates the IFN type I and III dependent retinal immune interaction and downregulates PD-L1 in the oBRB by a protease-dependent mechanism, potentially contributing to immune evasion and inflammation in retinal infection. Our results can pave the way to fully elucidate retinal immune networks and PD-L1 regulation mechanisms, offering potential targets for therapeutic interventions in OT and other retinal inflammatory diseases.
    Keywords:  PD-L1; Toxoplasma gondii; immune privilege; interferons; ocular toxoplasmosis; retina
    DOI:  https://doi.org/10.3389/fimmu.2025.1607247
  10. Results Probl Cell Differ. 2025 ;75 3-24
    Histone and Non-histone Reversible Acetylation in Development, Aging, and Disease.
    Sezgin Gunes, Neslihan Hekim, Sercan Ergun, Elzem Nisa Alkan, Cansu Can.
      Post-translational modifications (PTM) involve chemical modifications of amino acid residues within histone and non-histone proteins and are chemically diverse. PTM plays a vital role in regulating the chromatin structure in the nucleus, thus gene regulation. Among the various PTM, reversible acetylation of histone non-histone proteins has fundamental functions in various cellular processes. In all organisms, histone acetylation of lysine residues is connected with transcription activation. Acetyltransferases and deacetylases are well-known enzymes in the acetylation of the histone and non-histone proteins. This chapter will review the latest progress in histone and non-histone reversible acetylation epigenetic alterations and mechanisms and summarize how they affect development, aging, and diseases.
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_1
  11. J Enzyme Inhib Med Chem. 2025 Dec;40(1): 2520612
    Development of novel benzamide class I selective lysine deacetylase inhibitors as potent anticancer agents.
    Jason H Gill, Jonathan D Sellars, Paul G Waddell, Steven D Shnyder, Ronald Grigg, Colin W G Fishwick.
      Small molecule inhibitors of lysine deacetylases (KDACs), exemplified by histone deacetylases (HDACs), exhibit significant promise as cancer therapeutics. Using a modular combinatorial chemistry approach, a novel class of KDAC inhibitors (KDACi) containing the aminophenyl-benzamide headgroup have been developed, which incorporate a vinyl group within the linker region for active site stabilisation and a trifluoromethyl moiety within the capping group to exploit enzyme surface topology. Consequently, a class I selective KDACi (7) with a preference towards HDAC1 over other class I KDACs was identified. This KDACi orientates differently within the KDAC active site and exhibits an improved antitumour profile relative to the benchmark class I selective KDACi Entinostat (1). The clinical potential of 7 is further exemplified by the inhibition of tumour growth in an in vivo model of ovarian cancer. These results offer significant scope for the rational development of KDACi with improved selectivity against specific KDAC and widespread therapeutic potential.
    Keywords:  HDAC Inhibitor; Lysine Deacetylase (KDACs); aminobenzamide; benzamide; cancer chemotherapy; histone deacetylase (HDACs); protein acetylation
    DOI:  https://doi.org/10.1080/14756366.2025.2520612
  12. Results Probl Cell Differ. 2025 ;75 73-89
    Acetylation and Deacetylation of Cytoskeleton-Associated Proteins.
    Dale D Tang.
      The cytoskeleton of eukaryotic cells undergoes a reorganization in response to intracellular and extracellular cues, which plays an essential role in orchestrating various cell functions including migration, development, differentiation, tissue homeostasis, contractility, proliferation, gene expression, cancer cell invasion, and airway/vascular remodeling. Acetylation occurs on the cytoskeletal components, such as microtubules, actin, and vimentin, which regulate cellular functions. Moreover, remodeling of the cytoskeleton is regulated by acetylation and deacetylation of regulatory proteins, including adapter proteins and protein kinases. Therefore, protein acetylation and deacetylation are critical mechanisms for cytoskeletal reorganization in response to changes of intracellular and extracellular environments.
    Keywords:  Acetylation; Actin; Cytoskeleton; Intermediate filaments; Microtubules
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_3
  13. Cell Tissue Res. 2025 Jul 01.
    Enteroepithelial stages of Toxoplasma gondii in the ileum of cats by serial block face scanning electron microscopy.
    Marcia Attias, Wanderley de Souza, Jitender P Dubey.
      This study investigates the enteroepithelial stages of Toxoplasma gondii in the feline ileum using high resolution field emission scanning electron microscopy (FE-SEM) and serial block face scanning electron microscopy (SBF-SEM). By employing advanced imaging techniques, including creative sample processing methods, this research provides new insights into the development, distribution, and maturation of T. gondii within infected intestinal cells. Comparison with previous studies confirms earlier findings while offering enhanced resolution and three-dimensional models of the parasite's progression. SBF-SEM enabled the visualization of asexual forms of the parasite, from merozoites to multinucleated schizonts and rosettes, distributed along the intestinal villi. These observations suggest a tendency for merozoites to accumulate near the villus extrusion zone, where they are later released. Despite these advancements, the mechanisms of gamete fertilization and oocyst egress remain unresolved, highlighting key areas for future research.
    Keywords:  3-D reconstruction; Apicomplexa; Cat; Ileum; Merozoites; Schizonts; Serial block face scanning electron microscopy; Toxoplasma
    DOI:  https://doi.org/10.1007/s00441-025-03988-w
  14. Results Probl Cell Differ. 2025 ;75 363-390
    Reversible Acetylation of Non-histone Proteins in Human Cancers.
    Chunran Feng, Yiqun Zeng, Edward V Prochownik, Congqin Jiang, Youjun Li.
      Over the last three decades, we have witnessed great progress in uncovering the scope of reversible acetylation of non-histone proteins and understanding its mechanisms and functional consequences. In this review, we summarize the histone acetyltransferases (HATs)/deacetylases (HDACs) and their inhibitors, focusing on the role of reversible acetylation modification of non-histone proteins in tumor development while also exploring the application of HAT and HDAC inhibitors in cancer therapy.
    Keywords:  Cancer therapy; Histone acetyltransferases; Histone deacetylases; Reversible acetylation of non-histone protein
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_13
  15. Results Probl Cell Differ. 2025 ;75 189-209
    Epigenetic Echoes: Decoding the Acetylation Journey from Neural Crest to Melanocyte.
    Ayesha Nasreen, Sribas Chowdhury, Dharani Alagar Selvam, Vivek T Natarajan.
      Epigenetic mechanisms influence early developmental events, shaping gene expression in exciting ways that go beyond the DNA blueprint. The state of chromatin is governed by an interplay between various histone modifications, variants, nucleosome remodeling complexes, and other chromatin modifiers that work in sync to prime the chromatin for specific biological outcomes. In this chapter, we explore neural crest cells (NCCs), a critical progenitor population that retains the extensive developmental potential of their blastula origins. The formation and differentiation of NCCs into diverse cell types are influenced by the regulation of their acetylation state through various epigenetic factors. This chapter delves into the intricate interplay between histone acetylases (HATs) and deacetylases (HDACs), highlighting how these enzymes modify chromatin to create a permissive environment for the induction of NCCs and steer their fate toward the melanocytic lineage. The shift in acetylation profiles during the transition from melanocytes to melanoma suggests that the transcriptional machinery may override normal regulatory mechanisms, promoting a neural crest-like state in melanoma development. Epigenetic regulation, particularly through histone acetylation, plays a pivotal role in neural crest cell development and melanoma initiation offering potential therapeutic targets.
    Keywords:  H3K27 acetylation; Histone deacetylases (HDACs); MITF; Melanocytes; Melanoma; Neural crest cells (NCCs); p300
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_7
  16. Epidemiol Infect. 2025 Jul 04. 153 e74
    Toxoplasma gondii infection risk among pregnant people and congenital toxoplasmosis incidence in Japan.
    Ko Nakajo, Hiroshi Nishiura.
      Acute infection with Toxoplasma gondii in pregnant people can lead to vertical transmission to the foetus and congenital toxoplasmosis. As part of risk assessment, the epidemiology of toxoplasmosis among pregnant people must be quantitatively elucidated. Herein, we investigated the risk of primary T. gondii infection during pregnancy in Japan, estimating the incidence of T. gondii infection among pregnant people as well as that of congenital toxoplasmosis. We used a compartment model that captured the infection dynamics in pregnant people, analysing prescription data for spiramycin in Japan, together with local serological testing results and the screening rate of primary T. gondii infection during pregnancy. The nationwide risk of T. gondii infection pregnant people in Japan was estimated to be 0.016% per month. Among prefectures investigated, the risk estimate was highest in Tokyo with 0.030% per month. Nationally, the number of T. gondii infections among pregnant people in the years 2019, 2020, and 2021 was estimated to be 1507, 1440, and 1388 infections, respectively. The nationwide number of cases of congenital toxoplasmosis in each year was estimated at 613, 588, and 567 cases, respectively. Our study indicated that T. gondii infection continues to place a substantial burden on public health in Japan.
    Keywords:  Japan; epidemiology; pregnancy; statistical model; toxoplasma gondii; toxoplasmosis
    DOI:  https://doi.org/10.1017/S0950268825100150
  17. Eur J Med Res. 2025 Jul 04. 30(1): 571
    The role of HDAC6 in fibrosis: a novel and effective therapy strategy.
    Liangliang Zheng, Xiaoyan Zhu, Jiankui Du, Yujian Liu.
      Fibrosis is the usual pathological process observed across a broad spectrum of diseases. The mechanisms of fibrosis involve various cells and signaling pathways. Epigenetic regulation, such as histone acetylation, is one of the mechanisms. Among histone deacetylases (HDACs), histone deacetylase 6 (HDAC6) is particularly unique due to its two-domain structure and its presence in the cytoplasm. Apart from its well-known role as a histone modifier, HDAC6 interacts with multiple non-histone substrates, including α-tubulin, heat-shock protein 90 (HSP90), peroxiredoxins, and TGF-β. It also interacts with ubiquitin through noncatalytic functions. Elevated expression of HDAC6 has been observed in fibrotic diseases. Fibrosis is closely related to inflammation. Given that HDAC6 plays the unique link role in both fibrosis process and inflammation, HDAC6 inhibitors represent a new and effective maneuver for addressing fibrotic diseases. In this paper, we review recent advances in understanding the role of HDAC6 in fibrotic diseases affecting multiple organs, including the lung, heart, liver, kidney, and peritoneum. We also examine the effects of HDAC6 inhibitors, providing a valuable reference for future research into fibrosis mechanisms and therapeutic drug development.
    Keywords:  Deacetylation; Epigenetic regulation; Fibrosis; HDAC6; Therapeutic strategy
    DOI:  https://doi.org/10.1186/s40001-025-02840-9
  18. Results Probl Cell Differ. 2025 ;75 213-246
    Impact of Histone Acetyltransferases and Histone Deacetylases on Adult Brain Myelin Plasticity.
    Alessandra Dominicis, Tommaso Fabiano, Simone Peria, Aland Ibrahim Ahmed Al Jaf, Antonella Ragnini-Wilson.
      Myelin plasticity is a key process for acquiring new motor skills and preventing neurodegeneration during ageing. Neural precursor cells (NPCs) and parenchymal oligodendrocyte precursor cells (OPCs) play a key role in myelin plasticity in the central nervous system (CNS), being specialized in reconstituting the myelin sheath upon damage. Reversible acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) activity, controls these stem cells' differentiation in myelinating oligodendrocytes (mOLs) during their proliferation and remyelination processes. By modulating cytosolic protein activity and precisely orchestrating the spatial and timely regulated activity of the transcription factors participating in the NPC and OPC differentiation process, these enzymes play a vital role in preserving the adult brain's cognitive capacity during ageing. This review highlights the role of reversible acetylation in the regulation of stem cell differentiation during remyelination, as disruptions in this process contribute to severe neurodegenerative impairments and accelerated ageing.
    Keywords:  Acetylation; Differentiation; Epigenetics; HATs; HDACs; Histone; Neurodegeneration; Neurodevelopment; Oligodendrocytes
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_8
  19. PLoS Pathog. 2025 Jul 03. 21(7): e1012832
    Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages.
    María Pía Alberione, Yunuen Avalos-Padilla, Gabriel W Rangel, Miriam Ramírez, Tais Romero-Uruñuela, Àngel Fenollar, Jonathan Ortega-Barrionuevo, Marcell Crispim, Terry K Smith, Manuel Llinás, Luis Izquierdo.
      UDP-N-acetylglucosamine (UDP-GlcNAc) is a crucial sugar nucleotide for glycan synthesis in eukaryotes. In the malaria parasite Plasmodium falciparum, UDP-GlcNAc is synthesized via the hexosamine biosynthetic pathway (HBP) and is essential for glycosylphosphatidylinositol (GPI) anchor production, the most prominent form of protein glycosylation in the parasite. In this study, we explore a conditional knockout of glucosamine-6-phosphate N-acetyltransferase (PfGNA1), a key HBP enzyme. PfGNA1 depletion led to significant disruptions in HBP metabolites, impairing GPI biosynthesis and causing mislocalization of the merozoite surface protein 1 (MSP1), the most abundant GPI-anchored protein in the parasite. Furthermore, parasites were arrested at the schizont stage, exhibiting severe segmentation defects and an incomplete rupture of the parasitophorous vacuole membrane (PVM), preventing egress from host red blood cells. Our findings demonstrate the critical role of HBP and GPI biosynthesis in P. falciparum asexual blood stage development and underscore the potential of targeting these pathways as a therapeutic strategy against malaria.
    DOI:  https://doi.org/10.1371/journal.ppat.1012832
  20. Bioorg Chem. 2025 Jun 20. pii: S0045-2068(25)00580-2. [Epub ahead of print]163 108700
    Hydroxamic acid hybrids as histone deacetylase inhibitors for cancer therapy: an update (2022 to date).
    Yanjing Cheng, Yafei Zhuang, Ni Zhu, You Yu, Meichun Hu.
      Hydroxamic acid derivatives can specifically bind to the active site of histone deacetylases (HDACs), preventing the deacetylation of histones. This results in the relaxation of chromatin structure, allowing transcription factors to access DNA and activate the expression of tumor-suppressor genes, which helps to inhibit tumor cell growth and induce apoptosis. Recent research indicates that hybridizing various anticancer pharmacophores with a hydroxamic acid moiety can either enhance their inhibitory activity against HDACs or enable them to function as multi-targeting HDAC inhibitors. This approach capitalizes on the zinc-binding ability of hydroxamic acids, a key feature in HDAC inhibition, to create more effective and versatile anticancer agents. By integrating diverse pharmacophoric elements, these hybrids may address drug resistance and broaden their utility in cancer treatment. The strategy underscores the potential of molecular hybridization in rational drug design for developing next-generation HDAC-targeted therapeutics. This review outlines the current status of hydroxamic acid hybrids developed from 2022 onwards as potential HDAC inhibitors for cancer therapy, aiming to open new avenues for exploring novel candidates.
    Keywords:  Cancer; Histone deacetylases; Hybrids; Hydroxamic acid; Mechanisms of action; Structure-activity relationships
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108700
  21. Microbiol Spectr. 2025 Jun 30. e0328824
    Characterization of the malaria parasite Plasmodium falciparum Tepsin homolog.
    Stéphanie Roucheray, Maria R Narciso, Dave Richard.
      Plasmodium parasites rely on the invasion of human erythrocytes for their survival. This invasion process is facilitated by specialized organelles (rhoptry, micronemes, and dense granules) housed within a distinctive structure known as the apical complex. How the apical complex is generated is still enigmatic, especially how specificity is achieved in the vesicular trafficking between the Golgi apparatus and the apical organelles, but phosphoinositide lipids might potentially be involved. Here, we describe the characterization of a putative phosphoinositide-binding protein containing an Epsin NH2-terminal homology (ENTH) domain, Pf3D7_1459600. We show that this protein is structurally homologous to human Tepsin. Surprisingly, unlike other Tepsins, the ENTH domain of PfTepsin binds non-specifically to phosphoinositides in vitro, potentially through a positively charged pocket. Colocalization assays revealed that PfTepsin potentially transits between the Golgi apparatus and some of the apical organelles in developing schizonts. Finally, we provide evidence that PfTepsin potentially interacts with members of the clathrin and adaptor protein 4 complexes.IMPORTANCEMalaria takes an enormous toll on affected societies, and new drugs are urgently required. Understanding how the parasite causing malaria replicates could lead to potential new drug targets. Our work characterizes a protein called Tepsin that could potentially be important for the parasite to generate organelles critical for its survival.
    Keywords:  Golgi; Tepsin; malaria; protein trafficking
    DOI:  https://doi.org/10.1128/spectrum.03288-24
  22. Am J Ophthalmol Case Rep. 2025 Sep;39 102364
    Presumed bilateral endogenous Cryptococcus neoformans endophthalmitis with concomitant Toxoplasma gondii retinochoroiditis.
    Shane Griffin, Neeraj Chawla, Lawrence Chan, Anita Agarwal, Gaurav Shah.
       Purpose: To report a case of bilateral endogenous Cryptococcus endophthalmitis with Toxoplasma retinochoroiditis.
    Observations: A 57-year-old woman with history of renal transplantation developed Cryptococcus neoformans fungemia and meningitis. Reporting bilateral blurry vision, she was found to have associated bilateral endophthalmitis suspicious for endogenous cryptococcal endophthalmitis that was initially responsive to intravitreal voriconazole injections but subsequently worsened despite systemic and intraocular anti-fungal treatments. Given her refractory disease, additional testing was performed, which revealed added infection with Toxoplasma gondii. She underwent bilateral vitrectomy with povidone-iodine infusion and systemic parasiticidal treatment with improvement and stability of her condition.
    Conclusions and importance: Immunocompromised hosts are at risk for infection with multiple opportunistic infections that may require broad testing and aggressive medical and surgical therapies.
    Keywords:  Cryptococcus neoformans; Endogenous endophthalmitis; Immunocompromised; Opportunistic infection; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.ajoc.2025.102364
  23. Results Probl Cell Differ. 2025 ;75 91-140
    Tubulin Acetylation: A Critical Regulator of Microtubule Function.
    Inês L S Delgado, Bruno Carmona, Sofia Nolasco, Rita Marques, João Gonçalves, Helena Soares.
      The cytoskeleton is conserved throughout the eukaryotic lineage and consists of a complex dynamic network mainly composed of three distinct polymers: microtubules (MTs), actin filaments, and intermediate filaments. MTs are polymers of α/β-tubulin heterodimers, playing a myriad of distinct cellular functions and are the main components of complex structures like the mitotic spindle, cilia, and centrioles. Post-translational modifications (PTMs) regulate the function and increase the complexity of the α/β-tubulin heterodimer pools. One of the PTMs that has been extensively studied is the acetylation of lysine 40 (K40) on α-tubulin, which specifically occurs inside the MT lumen.Acetylation plays a crucial role in controlling the stability and function of MTs, in response to signals from within and outside the cell. It impacts the cytoplasm's 3D arrangement and important cellular activities like intracellular transport, cell division, polarity, and migration. Recent research has also emphasized the significance of this PTM in regulating the mechanical properties of MTs and cellular sensing. The levels and activity of MT acetyltransferases and deacetylases are tightly regulated through various transcriptional, post-transcriptional, and post-translational mechanisms, including miRNAs, phosphorylation, protein-protein interactions, and regulated localization between the nucleus and cytoplasm. These regulatory processes involve components of diverse signaling pathways, and their deregulation has been implicated in numerous diseases, including neurological disorders, cancer, and cardiac conditions.
    Keywords:  Microtubules; Post-translational modifications; Tubulin acetylation; Tubulin acetylation-related diseases; Tubulin lysine acetyltransferases; Tubulin lysine deacetylases
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_4
  24. Endocr Connect. 2025 Jul 01. pii: EC-25-0260. [Epub ahead of print]
    Targeting negative phosphorylation to activate AMPK.
    Alexia Pearah, Balamurugan Ramatchandirin, Karina Ramirez, Sally Radovick, Fredric E Wondisford, Ling He.
      AMPK is a master regulator of metabolism and is highly conserved and ubiquitously expressed. Activation of AMPK stimulates the catabolic pathway (glucose utilization and β-oxidation) and inhibits the anabolic pathway (gluconeogenesis, protein synthesis, and lipogenesis), leading to improvement of cellular energy status. However, the mechanisms of maintaining low cellular AMPK activity are not fully understood. We and other investigators showed that activated PKA in the glucagon-cAMP signaling pathway and insulin-activated AKT both can directly phosphorylate AMPKα1/2 at S496/491 to inhibit AMPK activity. In current study, we found that activation of AMPK by an activator AICAR led to elevated and prolonged phosphorylation of AMPKα1/2 at S496/S491, reflecting a feedback inhibition of AMPK activity. In in vitro assay, functional AMPKα1β1γ1 or AMPKα2β1γ1 can phosphorylate AMPKα1at S496 or AMPKα2 at S491, respectively. We designed and successfully screened a new AMPKα2 targeting-peptide to activate AMPK through competitively blocking the negative phosphorylation, resulting in suppression of gluconeogenic gene expression and promotion of mitochondrial fission in hepatocytes.
    DOI:  https://doi.org/10.1530/EC-25-0260
  25. Results Probl Cell Differ. 2025 ;75 391-410
    Lysine Acetyltransferase 6 Complexes in Neurodevelopmental Disorders and Different Types of Cancer.
    Negar Mousavi, Xiang-Jiao Yang.
      Lysine acetylation is a critical post-translational modification that regulates gene expression and cellular functions. The MYST family lysine acetyltransferases KAT6A (also known as MOZ and MYST3) and KAT6B (a.k.a. MORF and MYST4), in complex with the multivalent epigenetic regulator BRPF1, play key roles in hematopoietic and neural development. Dysregulation of these complexes is implicated in neurodevelopmental disorders, such as Genitopatellar and Say-Barber-Biesecker-Young-Simpson syndromes, as well as in various cancers, including leukemia and medulloblastoma. The evolutionary conservation of these complexes in Drosophila melanogaster and Caenorhabditis elegans underscores their fundamental biological significance. Understanding the structural and functional mechanisms of KAT6-BRPF1 complexes provides insight into their pathological roles and therapeutic potential.
    Keywords:  Acylation; Cancer; ClinVar variant; Germline mutation; Histone acetylation; Neurodevelopmental disorder; Somatic mutation
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_14
  26. Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00296-7. [Epub ahead of print]37(7): 1455-1456
    Muscle needs NAD, but how much?
    David W Frederick, Joseph P McGaunn, Joseph A Baur.
      Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of Cell Metabolism, Chubanava et al.1 use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.001
  27. Results Probl Cell Differ. 2025 ;75 329-361
    Acetylation in Viral Infection and Disease.
    Matloob Husain.
      Viruses are acellular organisms and part of our ecosystem but exist at the interface of living and non-living. Furthermore, viruses are obligate intracellular parasites hence require the machinery of other organisms to multiply. Consequently, most viral infections result into a viral disease. Broadly, viruses cause two types of infection-acute and persistent (latent and chronic), in humans and other mammals that could lead to various lethal and non-lethal viral diseases. Acetylation is now known to be a ubiquitous protein (and nucleic acid) modification and is critical for cellular metabolism. An imbalance in acetylation has been associated with various cancers and diseases in humans. Likewise, the association of acetylation with viral infection and disease was observed soon after its discovery in twentieth century. Now, the literature accumulated in this space shows that acetylation promotes the infection of many viruses causing both acute and persistent infections. Furthermore, reduction in the acetylation level reduces viral clearance from the host and promotes viral persistency. The latter can be interrupted by increasing the acetylation level by using deacetylase inhibitors. Indeed, this approach has become a therapeutic tool to treat and clear the persistent viral infections as well as boost the oncolytic virus-mediated cancer therapy.
    Keywords:  Acetylation; Acute; Antiviral; HATs; HDACs; Infection; Latency; Persistent; Proviral; Virus
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_12
  28. Neurochem Res. 2025 Jun 30. 50(4): 220
    Palmitic Acid Induces Dynamic Time-Dependent Alterations in HDACs, Neuronal Chromatin Acetylation, and Gene Expression.
    Saúl Santiago Rueda-Díaz, Iker Francisco Soto-Santarriaga, Karla Torres-Arciga, Valeria Melissa García-Cruz, Rodrigo González-Barrios, Manuel Flores-León, Clorinda Arias.
      Chronic consumption of high fat diets (HFD) is a risk factor for the development of metabolic diseases such as obesity and diabetes, and it is also associated with cognitive impairment and Alzheimer´s disease. Palmitic acid (PA) is a major component of HFD, and high concentrations of this saturated fatty acid exerts pleiotropic actions in cells. The PA effects have been largely studied in peripheral tissues where is considered a driving force for the development of many metabolic diseases such as obesity, insulin resistance and Type II diabetes. In the brain, particularly in neurons, it is able to increase oxidative metabolism, induce insulin resistance, and alter gene expression. However, little is known about how PA-induced metabolic alterations may affect gene expression mechanisms in neurons. One of the most studied PA-dependent mechanisms is associated with the lipid-induced activation of the transcription factors, PPAR-γ and PGC-α, but fewer studies have analyzed the PA-dependent regulation of epigenetic mechanisms. In this study, we identified PA-linked changes in the class I histone deacetylases (HDACs) content associated with chromatin acetylation and with differential expression of the BDNF-encoding gene and the non-coding retrotransposon, LINE1 in differentiated human neuroblastoma cells.
    Keywords:   BDNF ; HDACs; High fat diets; Histone acetylation; Palmitic acid
    DOI:  https://doi.org/10.1007/s11064-025-04469-w
  29. Methods Mol Biol. 2025 ;2929 53-69
    High-Throughput Post-Translational Modification Analyses by Reverse Phase Protein Array.
    Zhongcheng Shi, Michael Hoang Nguyen, Yuan Yao, Shixia Huang.
      Post-translational modifications play a crucial role in regulating protein functions by chemically modifying amino acids without altering underlying protein sequences. Protein modifications are highly involved in cellular signal transduction pathways that require swift changes between active and inactive states. Various methods, including reverse phase protein array (RPPA), have been developed to comprehensively assess the proteomic profile. RPPA technology, a robust antibody-based platform, can detect not only protein expression but also modifications, such as phosphorylation, methylation, and acetylation. This chapter presents the detailed RPPA protocol for profiling post-translational modifications, including protein phosphorylation using whole cell lysates and histone modifications using purified histones.
    Keywords:  Antibody-based proteomics; High throughput; Histone; Phosphorylation; Post-translational modification; Reverse phase protein array
    DOI:  https://doi.org/10.1007/978-1-0716-4595-6_5
  30. Results Probl Cell Differ. 2025 ;75 411-434
    Bromodomain and PHD Finger-Containing Protein 1: From Functions to a Developmental Disorder, Cancer, and Therapeutics.
    Arezousadat Razavi, Paulina Varela-Castillo, Xiang-Jiao Yang.
      Bromodomain and PHD finger-containing protein 1 (BRPF1) is an essential epigenetic regulator and plays a key role in post-translational modification of histones. It is a chromatin reader that recognizes acetylated histones and interacts with the paralogous lysine acetyltransferases KAT6A and KAT6B to promote histone acetylation and related acylations, such as propionylation, at lysine 23 of histone H3, thereby influencing gene expression and regulating developmental programs. BRPF1 contributes to a variety of cellular processes such as cell cycle progression, cell proliferation, cell differentiation, and responses to cellular stresses, including DNA damage. Moreover, BRPF1 is implicated in hematopoiesis, embryonic development, skeletal development, neurodevelopment, neurogenesis, learning, and memory. BRPF1 gene knockout in mice leads to severe bone marrow failure, anemia, and eventual death in a few weeks after birth. This review provides a brief overview of BRPF1 and its contribution to the molecular structure and biological functions of KAT6A and KAT6B complexes. We will explore the emerging evidence linking BRPF1 dysfunction to human diseases, particularly cancer and abnormal neurodevelopment, to highlight promising therapeutic opportunities for treating associated pathology.
    Keywords:  Acylation; Cancer; ClinVar variant; Germline mutation; Histone acetylation; Neurodevelopmental disorder; Somatic mutation
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_15
  31. Leukemia. 2025 Jun 30.
    SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.
    Moran Wang, Ruiqi Zhu, Donald Small, Lan Lin, Li Li, Shengling Ma, Linghui Xia, Shanshan Luo, Wenjuan He, Jianming Yu, Junying Li, Ruowen Wei, Ao Zhang, Wei Shi, Yu Hu.
      Metabolic reprogramming is a key focus of targeted therapies in acute myeloid leukemia (AML). The mitochondrial sirtuin SIRT5 removes succinyl groups from specific lysines and impacts cell metabolism, but its role in AML tumorigenesis has not been extensively explored. A recent study highlighted that SIRT5 regulates AML cell activity by modulating glutamine metabolism, but its molecular targets in AML remain unclear. This study aims to identify the substrates of SIRT5 in AML. It was found that a total of 83 proteins with 121 lysine (K) residues showed increased succinylation after SIRT5 knockdown, as determined by succinylome analysis of MOLM-13 cells. SIRT5 was validated to interact with HADHA, a key molecule in the fatty acid oxidation pathway. Knockdown of SIRT5 resulted in hypersuccinylation and reduced enzymatic activity of HADHA. Mimetic mutations of lysine indicated that SIRT5 desuccinylates HADHA at K644. Inhibiting SIRT5 or HADHA increased sensitivity to venetoclax (VEN) in both VEN-sensitive and VEN-resistant cell lines. SIRT5 knockdown enhanced VEN-mediated suppression of mitochondrial metabolism and improved the survival of AML-transplanted NSG mice when combined with VEN. This study reveals the role of SIRT5 in AML metabolic regulation and provides valuable insights for developing SIRT5-targeted drugs and combination therapies with metabolic inhibitors.
    DOI:  https://doi.org/10.1038/s41375-025-02673-9
  32. Results Probl Cell Differ. 2025 ;75 247-290
    Acetylation in Cardiac Aging: Molecular Mechanism and Therapeutic Approaches.
    Aditi Dattatraya Hase, Sanjay K Banerjee.
      This chapter highlights the hallmarks of cardiac aging, distinguishing characteristics between cardiac aging and cardiac senescence. An overview of the molecular mechanisms underlying cardiac aging, with a particular focus on the role of reversible protein acetylation, emphasizes the role of sirtuins in regulating heart function and structure. The chapter explores how alterations in energy metabolism contribute to heart dysfunction, with a focus on the impact of mitochondrial dysfunction and phenomena of protein acetylation, along with the role of acetylase and deacetylase in an aging heart. Additionally, the chapter discusses the regulation of cardiomyocyte proliferation and the potential for enhancing cardiac regeneration. Finally, therapeutic strategies, including caloric restriction and HDAC inhibitors, microRNAs, stem cells, and other pharmacological agents are examined as potential approaches to slow or reverse the effects of cardiac aging.
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_9
  33. Results Probl Cell Differ. 2025 ;75 141-162
    Tubulin Acetylation and the Cellular Mechanosensing and Stress Response.
    Bruno Carmona, Inês L S Delgado, Sofia Nolasco, Rita Marques, João Gonçalves, Helena Soares.
      Microtubule (MT) acetylation has emerged as a critical regulator of cellular stress responses, integrating mechanical and oxidative stimuli to support cellular adaptability and survival. This post-translational modification (PTM) enhances MT flexibility and resilience, enabling cells to withstand mechanical challenges such as changes in extracellular matrix stiffness and applied forces. Through its impact on MT physical properties, acetylation minimizes cytoskeletal breakage, reducing the need for constant remodeling and supporting cellular integrity under mechanical stress. Furthermore, tubulin acetylation regulates intracellular trafficking by modulating interactions with molecular motors, allowing for efficient cargo transport and precise spatial organization without disrupting the MT network. In the context of oxidative stress, tubulin acetylation responds to redox imbalances by stabilizing MTs and influencing cellular pathways that regulate reactive oxygen species (ROS). This modification is linked to enhanced antioxidant responses, autophagy regulation, and mitochondrial dynamics, highlighting its role in maintaining cellular homeostasis under oxidative conditions. The dual function of tubulin acetylation, responding to and integrating signals from mechanical and oxidative stress, acts as a bridging mechanism between physical and chemical signaling pathways. Consequently, it has the potential to be a therapeutic target in diseases characterized by dysregulated stress responses, including neurodegenerative disorders, cancer, and cardiovascular conditions. Despite significant progress has been made, unanswered questions persist, particularly regarding the molecular mechanisms by which acetylated MTs encode spatial and functional information and their interplay with other tubulin PTMs.
    Keywords:  Mechanical stress; Microtubule; Oxidative stress; Tubulin acetylation; Tubulin post-translational modifications
    DOI:  https://doi.org/10.1007/978-3-031-91459-1_5
  34. Bioorg Med Chem Lett. 2025 Jun 26. pii: S0960-894X(25)00227-6. [Epub ahead of print]127 130318
    Histone deacetylase 6 inhibitors in Alzheimer's disease therapy: structure design and challenges.
    Baiyun Dang, Hou Chen, Shiru Liu, Haijuan Liu, Zhiwen Kang, Zhen Yang, Weixia Yang, Jiadong Hu, Xin Chen.
      Recently, histone deacetylases 6 (HDAC6) has been extensively studied for involvement in pathogenesis of central nervous system (CNS) diseases, especially for Alzheimer's disease (AD). A lot of literatures have disclosed that HDAC6 inhibitors (HDAC6is) are effective and promising in AD treatment. Though many HDAC6is were reported, only a handful of them displayed appropriate in vivo activities in models of neurological diseases. BBB permeability and off-target toxicity are the major obstacle and challenge for the development of available HDAC6is. In this review, we summarized recent brain-permeable HDAC6is from drug design perspective, and discussed the challenges and structural modification attempts in developing HDAC6is with better blood-brain barrier (BBB) permeability.
    Keywords:  AD; HDAC6; Permeability; Selectivity; Structure design
    DOI:  https://doi.org/10.1016/j.bmcl.2025.130318
  35. Infect Drug Resist. 2025 ;18 3149-3155
    Detection of Toxoplasma gondii and High-Risk Human Papillomaviruses in FFPE Malignant and Benign Breast Lesions Using Real-Time PCR.
    Selma Usluca, Ayfer Bakir, Ata Türker Arikok, Gizem Korkut, Gulsah Ceylan Yagiz, Murat Alper.
       Objective: Breast cancer is the most prevalent malignancy among women. In recent years, it has been suggested that various pathogens such as Toxoplasma gondii (T. gondii) and human papillomavirus (HPV) may play a potential role in the development of breast cancer. This study aimed to determine the prevalence of T. gondii and HPV infections in formalin-fixed paraffin-embedded tissue samples of breast cancer patients using real-time PCR.
    Methods: The study included 136 paraffin-embedded biopsy samples with w confirmed malignant breast tumor diagnosis and 50 breast tissue samples diagnosed as benign breast lesions, serving as controls. The presence of T. gondii DNA and high-, medium-, and low-risk HPV genotype DNAs were investigated using the real-time PCR method. First, deparaffinization was performed using xylene and alcohol, followed by DNA extraction and real-time PCR amplification.
    Results: The most common histopathological types of malignant breast carcinoma were invasive carcinoma (n=82; 60.3%), invasive lobular carcinoma (n=26; 19.1%), invasive ductal carcinoma (n=8; 5.9%), and mixed invasive carcinoma (n=8; 5.9%). According to the Modified Bloom-Richardson classification, 55.15% of malignant breast tumor samples were grade 2, 32.4% were grade 3, and 12.5% were grade 1. Real-time PCR analysis did not detect T. gondii DNA or HPV DNA in any of these samples.
    Conclusion: Our findings do not support a role of T. gondii and HPV in breast cancer development. To better understand the possible relationship between breast cancer and these pathogens, further studies with larger sample sizes, diverse diagnostic methods, and broder geographical coverage are necessary.
    Keywords:  PCR; Toxoplasma gondii; breast; cancer; high-risk human papillomaviruses
    DOI:  https://doi.org/10.2147/IDR.S523180
  36. Microb Cell. 2025 ;12 157-172
    Knocking out histidine ammonia-lyase by using CRISPR-Cas9 abolishes histidine role in the bioenergetics and the life cycle of Trypanosoma cruzi.
    Janaína de Freitas Nascimento, María Julia Barisón, Gabriela Torres Montanaro, Letícia Marchese, Rodolpho Ornitz Oliveira Souza, Letícia Sophia Silva, Alessandra Aparecida Guarnieri, Ariel Mariano Silber.
      Trypanosoma cruzi, the causing agent of Chagas disease, is the only known trypanosomatid pathogenic to humans having a complete histidine to glutamate pathway, which involves a series of four enzymatic reactions that convert histidine into downstream metabolites, including urocanate, 4-imidazolone-5-propionate, N-formimino-L-glutamate and L-glutamate. Recent studies have highlighted the importance of this pathway in ATP production, redox balance, and the maintenance of cellular homeostasis in T. cruzi. In this work, we focus on the first step of the histidine degradation pathway, which is performed by the enzyme histidine ammonia lyase. Here we determined the kinetic and biochemical parameters of the T. cruzi histidine ammonia-lyase. By generating null mutants of this enzyme using CRISPR-Cas9 we observed that disruption of the first step of the histidine degradation pathway completely abolishes the capability of this parasite to metabolise histidine, compromising the use of this amino acid as an energy and carbon source. Additionally, we showed that the knockout of the histidine ammonia lyase affects metacyclogenesis when histidine is the only metabolizable source and diminishes trypomastigote infection in vitro.
    Keywords:  Trypanosoma cruzi; amino acids metabolism; bioenergetics; histidine
    DOI:  https://doi.org/10.15698/mic2025.06.853
  37. Med Rev (2021). 2025 Jun;5(3): 256-259
    Histone lactylation as a driver of metabolic reprogramming and immune evasion.
    Qiaoting Cai, Wei Deng, Yutian Zou, Zhe-Sheng Chen, Hailin Tang.
      Lactate is the end product of glycolysis, and extensive research has shown that lactate participates in various pathophysiological processes. Along with associated hydrogen ions, lactate typically functions as an immunosuppressive negative factor and plays a crucial role in tumor metabolic reprogramming. The recently discovered lactylation is a novel epigenetic modification that, similar to other epigenetic modifications, modifies histones to alter chromatin spatial configuration, thereby affecting DNA accessibility and regulating gene expression. More importantly, the degree of lactylation is closely related to local lactate concentrations, establishing a link between epigenetics and metabolic reprogramming. During cellular metabolism, lactate accumulation promotes histone lysine lactylation in cancer cells and immune cells such as macrophages and T cells, playing an essential role in tumor immune evasion and resistance to immunotherapy. This paper details the role of lactylation modifications in cancer immune evasion and resistance to immunotherapy, providing novel therapeutic directions and targets for cancer treatment.
    Keywords:  cancer; histone lactylation; immune escape; immunotherapy resistance
    DOI:  https://doi.org/10.1515/mr-2024-0091
  38. Clin Exp Med. 2025 Jul 01. 25(1): 225
    SIRT1 as a masterful reciprocal regulator of molecular mechanisms and signaling pathways involved in tumor growth and expansion.
    Mehrdad Hashemi, Neda Zali, Seyedeh Zahra Ghafarzadeh Dastjerdi, Bita Pakshad, Melika Aliahmadi, Nafiseh Sharifi, Kimia Sadat Esfahani, Fatemeh Sadat Kohandani, Sogand Chamanian, Fariba Abbasi, Faranak Jamshidian, Afshin Taheriazam, Mina Alimohammadi, Payman Rahimzadeh, Najma Farahani, Maliheh Entezari.
      Sirtuin 1, which is more commonly identified as SIRT1, is a well-recognized NAD+-dependent histone and/or protein deacetylase that operates a wide range of cellular and molecular mechanisms involved in carcinogenic processes. SIRT1 not only regulates the primary mechanisms involved in tumorigenesis but also is responsible for controlling other processes, such as cell migration and metastasis, autophagy, and apoptotic flux, as well as chemotherapeutic resistance. It is well established that SIRT1 works at the upstream of signal transduction pathways, such as p53 signaling, together with FOXO mechanism, as well as the others. Indeed, SIRT1 by its deacetylase activity deacetylates different molecules in those signaling pathways and mostly causes a kind of blockade in the signaling of interest. Nonetheless, many aspects of SIRT1-cancer relationship are ambiguous, and more experiments should be performed for further uncovering of the concept. In the current review, we first highlight the major regulators of SIRT1 in cancer and then underscore key signal transduction pathways regulated by SIRT1. In the following, the role of SIRT1 will be discussed in tumor progression, from tumorigenesis to chemotherapeutic resistance, and at last, the contribution of SIRT1 to human cancers will be exemplified by some studies conducted in the field.
    Keywords:  Carcinogenesis; Drug resistance; Neoplasm; Signal transduction; Sirtuin 1
    DOI:  https://doi.org/10.1007/s10238-025-01759-z
  39. Nat Commun. 2025 Jul 01. 16(1): 5563
    Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
    Huiwang Zhan, Dhiman Sankar Pal, Jane Borleis, Yu Deng, Yu Long, Chris Janetopoulos, Chuan-Hsiang Huang, Peter N Devreotes.
      Although glycolysis is traditionally considered a cytosolic reaction, here we show that glycolytic enzymes propagate as self-organized waves on the membrane/cortex of human cells. Altering these waves led to corresponding changes in glycolytic activity, ATP production, and dynamic cell behaviors, impacting energy-intensive processes such as macropinocytosis and protein synthesis. Mitochondria were absent from the waves, and inhibiting oxidative phosphorylation (OXPHOS) had minimal effect on ATP levels or cellular dynamics. Synthetic membrane recruitment of individual glycolytic enzymes increased cell motility and co-recruited additional enzymes, suggesting assembly of glycolytic multi-enzyme complexes in the waves. Remarkably, wave activity and glycolytic ATP levels increased in parallel across human mammary epithelial and other cancer cell lines with higher metastatic potential. Cells with stronger wave activity relied more on glycolysis than on OXPHOS for ATP. These results reveal a distinct subcellular compartment for enriched local glycolysis at the cell periphery and suggest a mechanism that coordinates energy production with cellular state, potentially explaining the Warburg effect.
    DOI:  https://doi.org/10.1038/s41467-025-60596-6
  40. Biol Res. 2025 Jul 02. 58(1): 43
    FGA, a new target of histone acetylation, inhibits apoptosis of granulosa cells in follicles.
    Yongcai Chen, Ming Fang, Wenmiao Duan, Tiantian Yang, Haidan Fan, Meng Lv, Liuhong Zhang, Yao Jiang, Shuo Li, Nian Li, Jiaqi Li, Xiaolong Yuan.
      Granulosa cells (GCs) are the main supporting cells for follicles, and histone acetylation has been reported to regulate follicular development. However, the mechanism of histone acetylation regulating follicular development is still unclear in GCs. In this study, we found that FGA, fibrinogen alpha chain, mediated the survival and fate of GCs. Knockdowns of HDAC1 and HDAC3 significantly inhibited the mRNA level of FGA, while knockdown of HDAC2 notably decreased the protein level of FGA. Moreover, knockdown of HDAC2 repressed the chromatin accessibility and the enrichment level of H3K9ac at -1350/-1454 bp of FGA. In addition, FGA promoted GCs proliferation and cycle progression by up-regulating the expressions of PCNA and CCNE1, whereas it inhibited apoptosis by suppressing the expression of Caspase3. In vitro, FGA was likely to promote follicular development of pigs. In mice, FGA inhibited the apoptosis of GCs and increased the number of corpora lutea, as a result, elevating estradiol levels and advancing the day of pubertal initiation. Both in vitro and in vivo experiments, FGA promoted follicular development by up-regulating PCNA and CCNE1, while inhibited follicular apoptosis by down-regulating Caspase3 and Caspase9. Overall, knockdown of HDAC2 repressed transcription by reducing chromatin accessibility and decreasing H3K9ac binding at the FGA promoter. FGA inhibited apoptosis of GCs by suppressing the expression of Caspase3 and promoted follicular development. This study showed that FGA is a novel target for histone acetylation to regulate follicular development in mammals.
    Keywords:  Chromatin accessibility; FGA; Follicles; H3K9ac
    DOI:  https://doi.org/10.1186/s40659-025-00623-4
  41. PLoS Pathog. 2025 Jun;21(6): e1013294
    Complex interactions in the life cycle of a simple parasite shape the evolution of virulence.
    Luís M Silva, Jacob C Koella.
      Evolutionary expectations about the virulence of parasites (i.e., the parasite-induced mortality rate of the host) often focus solely on the within-host transmission stage, overlooking the time spent between hosts and variations in transmission cycles. Moreover, the parasite growth rate within the host is closely linked to virulence. Here, we suggest that a simplified view of transmission and parasite evolution makes predicting how virulence will evolve difficult. We illustrate our ideas with a parasite with a simple life cycle, the microsporidian Vavraia culicis, which infects the mosquito Anopheles gambiae. We selected the parasite over six host generations for early or late host transmission, corresponding to shorter or longer time within the host. Selecting for late transmission increased their exploitation of the host, resulting in higher host mortality and a shorter life cycle with rapid infective spore production, comparatively to selection for early transmission. In response, hosts infected with late-selected spores shortened their life cycle and shifted to earlier reproduction. Using different host harm metrics, we demonstrate and discuss the pros and cons of using different measures of virulence. These and other findings emphasize the importance of considering the entire transmission cycle in studies of parasite evolution and raise concerns about how host density and social settings might influence virulence evolution.
    DOI:  https://doi.org/10.1371/journal.ppat.1013294
  42. Sci Rep. 2025 Jul 02. 15(1): 23283
    A paternal lactate dehydrogenase critically enhances male gametogenesis and malaria transmission.
    Annie Z Tremp, Sadia Saeed, Johannes T Dessens.
      Malaria blood stage parasite development relies on glycolysis to generate ATP, which requires pyruvate to lactate conversion by an essential lactate dehydrogenase enzyme (LDH1). Conversely, parasites developing in the mosquito employ mitochondrial chemiosmosis for ATP production. The source of ATP during transition from vertebrate to insect is less clear; gametes form in the mosquito midgut lumen within minutes of gametocyte ingestion, and while female gametes possess a mitochondrion, this organelle is absent from male gametes (microgametes). Here, we investigate a second LDH enzyme (LDH2) found exclusively in male gametocytes and microgametes. Knockout of Plasmodium berghei LDH2 expression reduces the number and size of exflagellation centres and radically diminishes oocyst development in Anopheles stephensi mosquitoes. Our data indicate that LDH2 supplements LDH1 activity to facilitate the cytokinesis step of male gametogenesis, while LDH1 alone is sufficient for motility of free-swimming microgametes. Our results point to a key role for glycolytic ATP production in microgamete formation and function and identify LDH activity as a potential malaria transmission-blocking drug target.
    Keywords:  Gametogenesis; Glycolysis; Lactate dehydrogenase; Plasmodium; Transmission-blocking drugs
    DOI:  https://doi.org/10.1038/s41598-025-05832-1
  43. Cell Commun Signal. 2025 Jul 01. 23(1): 311
    Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.
    Mincong Shu, Yuhan Liu, Jianbin Wang.
      Serine is a non-essential amino acid, serving as a precursor for other amino acids, lipids, and nucleotide synthesis. Its supply is ensured by two main mechanisms: exogenous uptake and endogenous synthesis. The serine synthesis pathway (SSP) connects glycolysis with the one-carbon cycle and plays an important role in cellular homeostasis by regulating substance synthesis, redox homeostasis, and gene expression. The de novo SSP involves three successive enzymatic reactions catalyzed by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). Post-translational modifications (PTMs), as essential regulatory mechanisms of proteins, play pivotal roles in physiological and pathological processes. This review focuses on the regulatory mode of PTMs on PHGDH, PSAT1, and PSPH, including phosphorylation, ubiquitination, acetylation, methylation, S-palmitoylation, S-nitrosylation, deamidation, SUMOylation, and lactylation. We summarize how these PTMs participate in the metabolic reprogramming of SSP. It helps us better understand the molecular mechanisms and physiological significance of the PTM network in serine synthetic metabolism, providing guidance for subsequent research and development in the future.
    Keywords:  PHGDH; PSAT1; PSPH; Post-translational modification; Serine synthetic pathway
    DOI:  https://doi.org/10.1186/s12964-025-02327-4
  44. Front Biosci (Schol Ed). 2025 Jun 25. 17(2): 38998
    Inhibitory Effect of Novel Dihydroxamate Derivatives for Histone Deacetylase 1.
    Jhawn G Saul, Andrew E Huckleby, Maia C Gugello, Jonathan Urbanczyk, Staci Desmarais, Hyunshun Shin, Apparao Bokka, Junha Jeon, Jatindra N Tripathy, Sung-Kun Kim.
       BACKGROUND: Histone deacetylase 1 (HDAC1) is a critical epigenetic regulator involved in chromatin remodeling and transcriptional repression, making it a valuable target for cancer therapy. Selective inhibition of HDAC1 represents a promising approach to cancer treatment, as it modulates gene expression and induces apoptosis in tumor cells.
    METHODS: Two novel hydroxamate-based HDAC1 inhibitors, compounds 4 and 6, were designed and evaluated using molecular docking, molecular dynamics (MD) simulations, and enzymatic inhibition assays. Molecular docking assessed binding interactions, while MD simulations evaluated the stability of the ligand-protein complexes. Enzymatic inhibition assays were used to determine the IC50 values and evaluate the potency of the compounds.
    RESULTS: Molecular docking revealed that both compounds exhibited significant interactions with HDAC1, including hydrophobic contacts, hydrogen bonding, and zinc coordination. Compound 4 demonstrated a stronger binding affinity (-6.2 kcal/mol) compared to compound 6 (-5.7 kcal/mol). The MD simulations confirmed that compound 4 exhibited greater stability, with divalent zinc coordination (4.3 Å and 4.8 Å), whereas compound 6 showed weaker monovalent coordination (4.4 Å). Enzymatic assays demonstrated that compound 4 had an IC50 of 2.96 ± 0.4 μM, while compound 6 exhibited an IC50 of 4.76 ± 0.5 μM; thus, compound 4 possesses superior inhibitory potency.
    CONCLUSIONS: Compound 4 exhibits enhanced binding affinity, stability, and enzymatic inhibition compared to compound 6, suggesting that this compound may serve as a promising lead for the development of selective HDAC1 inhibitors.
    Keywords:  enzyme inhibitors; histone deacetylase 1; hydroxamic acids; molecular dynamics simulation
    DOI:  https://doi.org/10.31083/FBS38998
  45. Microbiol Spectr. 2025 Jun 30. e0009625
    Metabolomic analysis of the impact of MtrA on carbon metabolism in Streptomyces coelicolor.
    Yanping Zhu, Hanlei Zhang, Xiuhua Pang.
      The response regulator MtrA of Streptomyces regulates secondary metabolism as well as primary metabolism, including nitrogen metabolism and phosphate metabolism; however, it is not known whether MtrA is involved in the control of central carbon metabolism in Streptomyces. In this study, we revealed that the growth medium of the MtrA mutant strain (ΔmtrA) is acidic under multiple growth conditions and that this acidification is dependent on the type of medium used. We performed targeted metabolomic analysis to determine the types and levels of organic acids produced by the wild-type strain Streptomyces coelicolor M145 and ΔmtrA, and the results revealed that production of multiple organic acids associated with the tricarboxylic acid cycle (TCA) and glycolysis pathway was changed significantly in ΔmtrA, compared with M145, indicating a broad impact of MtrA on carbon metabolism and suggesting the basis for the acidification of the growth media by ΔmtrA. Multiple potential MtrA sites were predicted in the sequences upstream of genes involved in the TCA cycle, including genes encoding citrate synthases, and we showed that MtrA bound these potential sites, suggesting that MtrA targets these carbon metabolism genes. Our transcriptional analysis showed that carbon metabolism genes with MtrA sites are differentially expressed in ΔmtrA, indicating regulation of these genes by MtrA. Overall, our study indicates that the response regulator MtrA has a broad impact on central carbon metabolism, adding new insight into our understanding of the regulation of carbon metabolism in Streptomyces.IMPORTANCECentral carbon metabolism is a key primary metabolic process, and its tight regulation is crucial for maintaining normal physiology in microbes. However, carbon metabolism is the least understood metabolic process in primary metabolism in Streptomyces. In this study, we demonstrated a broad impact of the response regulator MtrA on the production of metabolites associated with the tricarboxylic acid cycle and glycolysis pathway, thereby leading to the accumulation of organic acids and decreases in the pH values of the growth medium with an MtrA mutant strain. We further revealed MtrA sites upstream of genes involved in carbon metabolism and determined that MtrA bound to these sites, revealing MtrA as a regulator for carbon metabolism in Streptomyces. Our study enhances the understanding of the role of MtrA and helps to elucidate the regulatory mechanisms of a major metabolic process in Streptomyces.
    Keywords:  MtrA; Streptomyces; carbon metabolism; organic acid
    DOI:  https://doi.org/10.1128/spectrum.00096-25
  46. NPJ Precis Oncol. 2025 Jun 28. 9(1): 206
    Epigenetic regulators in cancer therapy and progression.
    Hany E Marei.
      Heritable gene activity variations that do not alter the underlying DNA sequence are known as epigenetic modifications. Mutations that disrupt genome structure and function are key drivers of oncogenesis. In addition to genetic mutations that cause direct disruptions in the DNA sequence, epigenetic changes can affect gene expression, which helps the development of cancerous traits. Changes in DNA methylation and histone mark patterns are the main drivers of these epigenetic modifications, as they encourage the growth and spread of tumors. In this review, we explore the substantial implications of epigenetic control on tumor genesis, metastatic behaviour, metabolic pathways, and the tumor microenvironment, delving into the intricacies of this intricate regulation. We pay special attention to the dysregulation at every stage of epigenetic modulation, which includes, but is not limited to, abnormalities in the enzymes that modify histones and methylate DNA, subunit loss or fusions in chromatin remodeling complexes, and disruptions in higher-order chromatin structure. We also highlight the development of inhibitors of medications targeted at epigenetic enzymes and summarize the abnormal roles of enzymes in DNA methylation, histone acetylation, and histone methylation during tumour progression.
    DOI:  https://doi.org/10.1038/s41698-025-01003-7
  47. PLoS One. 2025 ;20(7): e0326238
    Lack of knowledge of stakeholders in the pork value chain: Considerations for transmission and control of Taenia solium and Toxoplasma gondii in Burundi.
    Salvator Minani, Jean-Bosco Ntirandekura, Koen Peeters Grietens, Anastasie Gasogo, Sarah Gabriël, Chiara Trevisan.
      Taenia solium and Toxoplasma gondii are important foodborne zoonotic parasites that cause substantial health and economic impacts worldwide. In Burundi, there was a lack of data on the knowledge, attitudes, and practices of stakeholders in the pork value chain. To fill this gap, this study aimed to assess the knowledge of stakeholders in the pork value chain regarding T. solium and T. gondii infections and identify health-seeking routes and factors contributing to parasitic transmissions. A mixed methods study was conducted in Bujumbura city, Kayanza, and Ngozi provinces from January 10 to April 27, 2023. Quantitative data was collected using questionnaire-based interviews with 386 participants, while qualitative data was gathered from 63 participants through focus group discussions, informal conversations, and observations. The majority of the participants in the quantitative study had heard about porcine cysticercosis (94.8%) and pork tapeworm (90.9%), although the transmission and symptoms of these diseases were less known (>60%) and inaccurately described. Most participants were not aware of human cysticercosis (96.4%), its association with epilepsy (78%), and T. gondii infections (91.2%). There was a low proportion of medical consultations for pork tapeworm (30.1%), epilepsy (36.5%), and toxoplasmosis (7%). The qualitative study supported the findings of the quantitative study, revealing low knowledge among participants and misconceptions about the causes, consequences, and treatment-seeking routes related to T. solium and T. gondii infections. The short roasting time of pork (<15 minutes) and low perception of the consequences of consuming pork infected with cysts exposed pork consumers to these parasitic infections. Inadequate knowledge about these parasitic infections, along with inadequate practices in treatment-seeking and pork preparation and consumption, can contribute to continued transmission and pose significant barriers to control programmes. Training and public health education following the One Health approach are urgently needed to better tackle these parasitic infections in Burundi.
    DOI:  https://doi.org/10.1371/journal.pone.0326238
  48. Biochem Soc Trans. 2025 Apr 30. 53(2): 497-507
    Regulation of neuronal ankyrin localization and function by post-translational modifications.
    Kalynn M Bird, Paul M Jenkins.
      Ankyrins are a family of intracellular scaffolding proteins that control the subcellular localization of a host of critically important signaling proteins within neurons, including many proteins associated with neurological disease. Ankyrin proteins are a vital component of the neuron. These scaffolding proteins must be spatially and temporally arranged to interact with their binding partners and facilitate proper neuronal signaling. Dysfunction of ankyrins is associated with neurodevelopmental disorders such as epilepsy and autism spectrum disorder. Despite the high degree of sequence similarity between ankyrin proteins, they display almost completely nonoverlapping localization and function. How ankyrins localize to the correct subcellular compartments to interact with their binding partners and complete their distinct roles remains poorly understood. Emerging evidence suggests that post-translational modifications may play a key part in this process. Some of the post-translational modifications that have been identified to regulate ankyrins are phosphorylation, ubiquitination, and palmitoylation. These modifications affect proper interactions, function, and localization of ankyrin proteins, which highlights their potential role in disease. This review will give an overview of neuronal ankyrins, and how post-translational modifications could be utilized to regulate protein localization and function in the context of neurological disease.
    Keywords:  ankyrin; neurodevelopmental disorders; palmitoylation; phosphorylation; protein localization; ubiquitination; voltage-gated sodium channel
    DOI:  https://doi.org/10.1042/BST20253016
  49. Drug Des Devel Ther. 2025 ;19 5489-5505
    Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction.
    Carola Castiello, Panagiotis Efentakis, Panagiota-Efstathia Nikolaou, Lydia Symeonidi, Christina Chania, Ioanna Barla, Ifigeneia Akrani, Nikolaos Kostomitsopoulos, Evangelos Gikas, Nikolaos S Thomaidis, Emmanuel Mikros, Petra Kleinbongard, Rossella Fioravanti, Clemens Zwergel, Sergio Valente, Antonello Mai, Ioanna Andreadou.
       Purpose: Sirtuins (SIRTs) play a critical role in redox and metabolic regulation of the myocardium; however, the cardioprotective potential of SIRT5 in terms of infarct size (IS) reduction is still elusive. Herein, we employed the newly synthesized SIRT5-specific agonist, MC3215, developed by our group, to explore for the first time the pharmacological activation of SIRT5 as a target for cardioprotection.
    Methods and Results: In in vitro screening experiments, SIRT1 and SIRT5 agonists, namely, MC2606 and MC3215, at 1-20 μΜ were added to cardiomyoblasts (H9c2) and human endothelial cells (EA.hy-926) during 24 h hypoxia/2 h reoxygenation (H/R). SIRT1 and SIRT5 agonists mitigated H/R injury. Male C57BL/6J mice underwent 30 min ischemia (I) followed by 2 h or 24 h reperfusion (R). Mice received vehicle, the SIRT1 or SIRT5 agonists at 20 and 30 mg/kg at the 20th min of ischemia, and IS was quantified via triphenyl-tetrazolium chloride staining (n=5-7/group). MC3215-mediated SIRT5 activation reduced IS at 24 h R at 20mg/kg compared to controls (25.18±2.7% vs 38.80±4.7%). MC3215 treatment resulted in reduced protein malonylation in all experimental settings. Targeted mass-spectrometry-based metabolomics in the ischemic heart at the 10th min of R suggested increased fatty acid oxidation, as indicated by increased N3-Trimethyllysine and D-pantothenate. Concomitantly, molecular analysis indicated that the SIRT5 agonist activated AMPKα and Reperfusion Injury Salvage Kinase (RISK) pathway. Additionally, at 3 h reperfusion, MC3215 led to increased mitofusin 2 without altering apoptosis, paving towards improved mitochondrial dynamics. Co-administration of SIRT5 inhibitor, TW-37, abrogated MC3215-mediated cardioprotection.
    Conclusion: SIRT5 pharmacological agonism emerges as a novel cardioprotective target, leading to RISK pathway activation and mitochondria-related metabolic effects, converging at salvaging ischemic myocardium from I/R injury.
    Keywords:  SIRT5; cardioprotection; myocardial ischemia/reperfusion injury; sirtuins
    DOI:  https://doi.org/10.2147/DDDT.S509337
  50. J Exp Clin Cancer Res. 2025 Jul 01. 44(1): 180
    Targeting glutamine metabolism as a potential target for cancer treatment.
    Wenxuan Zou, Zitao Han, Zihan Wang, Qian Liu.
      Metabolic reprogramming is a hallmark of cancer cells, and the advent of "glutamine addiction" in numerous tumors signifies a pivotal advancement for precision-targeted therapy. This review demonstrates that glutamine metabolism is a pivotal factor in the development of malignant phenotypes in tumors by modulating multifaceted regulatory networks (Hippo/YAP, mTORC1 signaling pathway, and non-coding RNAs). These networks play a crucial role in the reprogramming of glutamine metabolism, which in turn affects various hallmarks of cancer, including cancer cell proliferation, ROS-mediated inhibition of apoptosis, and EMT-associated invasive metastasis. With respect to targeted therapeutic strategies, the focus on key transporters and metabolizing enzymes (ASCT2/GLS1) provides a theoretical foundation for the development of multi-targeted combination therapeutic regimens based on the inhibition of glutamine metabolism. A body of research has demonstrated that the metabolic processes of glutamine regulate a variety of immune system functions, including T cell depletion/activation, the polarization of TAMs, and the function of NK cells. This regulatory relationship, termed the metabolic-immune axis, is a crucial factor in the development of immune escape mechanisms by tumors. The study further suggests that a combination of targeted intervention strategies, involving the modulation of glutamine metabolism, has the potential to reshape the immune microenvironment and enhance the efficacy of CAR-T cell therapy. It is important to note that glutamine metabolism also affects tumor stroma formation by remodeling cancer-associated fibroblasts (CAFs). In response to therapeutic resistance mechanisms, tumor cells form adaptive escapes through ASNS and GAD metabolic branch activation, glucose/lipid metabolic compensation, and ATF4 transcriptional stress networks. This review systematically integrates the critical role of glutamine metabolism in tumor development and therapeutic resistance, providing new perspectives and translational pathways for the development of precision therapeutic strategy selection based on metabolic plasticity modulation.
    Keywords:  Anticancer targets; Drug resistance; Glutamine metabolism; Immune evasion; Malignant progression of tumors
    DOI:  https://doi.org/10.1186/s13046-025-03430-7
  51. Virulence. 2025 Dec;16(1): 2521478
    Leishmania mexicana pathogenicity requires flagellar assembly but not motility.
    Tom Beneke, Rachel Neish, Carolina M C Catta-Preta, James Smith, Jessica Valli, Ciaran J McCoy, Andreia Albuquerque-Wendt, Jeremy C Mottram, Eva Gluenz.
      Protists of the order Trypanosomatida possess a single multifunctional flagellum, which powers cellular displacement and mediates attachment to tissues of the arthropod vector. The kinetoplastid flagellar cytoskeleton consists of a nine-microtubule doublet axoneme; further structural elaborations, which can vary between species and life cycle stages, include the assembly of axonemal dynein complexes, a pair of singlet microtubules and the extra-axonemal paraflagellar rod. The intracellular amastigote forms of Leishmania spp. build a short, non-motile cilium whose function has remained enigmatic. Here, we used a panel of 25 barcoded promastigote cell lines, including mutants lacking genes encoding flagellar assembly proteins, axonemal proteins required for normal motility, or flagellar membrane proteins to examine how these defects impact on their virulence in macrophages and mice. Mutants lacking the intraflagellar transport (IFT) protein 88 were avirulent indicating that assembly of a flagellum is necessary to allow for Leishmania survival in a mammalian host. A similarly severe loss of virulence was observed upon deletion of BBS2, a core component of the BBSome complex, which may act as a cargo adapter for IFT. By contrast, promastigotes that were unable to beat their flagella due to loss of core axonemal proteins could establish and sustain an infection and only showed a small reduction of parasite burden in vivo compared to the parental cell lines. These results confirm that flagellar motility is not necessary for mammalian infection, but flagellum assembly and the integrity of the BBSome are essential for pathogenicity.
    Keywords:  CRISPR screen; Leishmania; flagella; motility; virulence
    DOI:  https://doi.org/10.1080/21505594.2025.2521478
  52. Nat Commun. 2025 Jul 01. 16(1): 5502
    BAHCC1 binds H4K20me1 to facilitate the MCM complex loading and DNA replication.
    Dongxu Li, Zhi-Min Zhang, Liu Mei, Yao Yu, Yiran Guo, Samuel G Mackintosh, Jianbin Chen, David F Allison, Arum Kim, Aaron J Storey, Ricky D Edmondson, Stephanie D Byrum, Alan J Tackett, Ling Cai, Jeanette G Cook, Jikui Song, Gang Greg Wang.
      Mono-methylation of histone H4 lysine 20 (H4K20me1) regulates DNA replication, cell cycle progression and DNA damage repair. How exactly H4K20me1 regulates these biological processes remains unclear. Here, we report that an evolutionarily conserved tandem Tudor domain (TTD) in BAHCC1 (BAHCC1TTD) selectively reads H4K20me1 for facilitating replication origin activation and DNA replication. Our biochemical, structural, genomic and cellular analyses demonstrate that BAHCC1TTD preferentially recognizes H4K20me1 to promote the recruitment of BAHCC1 and its interacting partners, notably Mini-chromosome Maintenance (MCM) complex, to replication origin sites. Combined actions of the H4K20me1-reading BAHCC1 and the H4K20me2-reading Origin Recognition Complex (ORC) ensure genomic loading of MCM for replication. Depletion of BAHCC1, or disruption of the BAHCC1TTD:H4K20me1 interaction, reduces H4K20me1 levels and MCM loading, leading to defects in replication origin activation and cell cycle progression. In summary, this study identifies BAHCC1TTD as an effector transducing H4K20me1 signals into MCM recruitment to promote DNA replication.
    DOI:  https://doi.org/10.1038/s41467-025-61284-1
  53. Sci Rep. 2025 Jul 01. 15(1): 21359
    Functional characterisation of components in two Plasmodium falciparum Cullin-RING-Ligase complexes.
    Danushka Marapana, Simon A Cobbold, Michal Pasternak, Gerald J Shami, Stuart A Ralph, Sash Lopaticki, Jumana Yousef, Vineet Vaibhav, Laura F Dagley, David Komander, Alan F Cowman.
      Ubiquitination is the key eukaryotic post-translational modification that governs protein degradation, localisation, and activity which is mediated by a concerted enzyme cascade. The largest superfamily of these enzymes include the Cullin-RING-Ligase (CRL) complexes. Plasmodium falciparum, the causative agent of the most severe form of malaria in humans, encodes the critical proteins required for ubiquitination, but we do not yet understand the function of this pathway. Here the P. falciparum CRL complexes were characterised to reveal an essential but minimal repertoire controlled by two Cullin scaffolds. A PfCullin1-linked CRL complex, recruiting a single substrate receptor, was identified as being required for parasite inner-membrane biogenesis and DNA replication. A second CRL complex functioning through a PfCullin4 scaffold was identified that utilised a previously unidentified adaptor protein and receptors to support DNA replication. These results show that the P. falciparum CRL complexes are essential in both nuclear maintenance and membrane integrity.
    Keywords:   P. falciparum ; Cullin-ring-ligase; E3 ligase; Malaria; Ubiquitination
    DOI:  https://doi.org/10.1038/s41598-025-05342-0
  54. Vet Res. 2025 Jul 01. 56(1): 134
    Early dynamics of Toxoplasma gondii infection in sheep inoculated at mid-gestation with archetypal type II oocysts.
    Roberto Sánchez-Sánchez, Pilar Horcajo, Miguel Fernández, David Arranz-Solís, Natalia Velasco-Jiménez, Michela Re, Daniel Gutiérrez-Expósito, Guillermo Valdivia, Angela Alonso-Diez, Julio Benavides, Luis Miguel Ortega-Mora.
      Early abortion is a clinical presentation of ovine toxoplasmosis that occurs in the second week post-infection (pi), which is characterised by placental infarcts, foetal leukomalacia and absence of parasites in the placenta and foetal tissues. The pathogenic mechanism of early abortion is unknown, and descriptions of the early dynamics of T. gondii infection in pregnant sheep are scarce. The aim of this study was to investigate the presence of lesions and parasite DNA in the small intestine, mesenteric lymph nodes and placenta/foetus, that could be key during the first week after oral infection in sheep at mid-pregnancy. In the small intestine, lesions were rare and parasite DNA detection rates were low (3-8%), with the highest parasite DNA detection and burden found on day 6 pi in the Peyer's patches of the medial jejunum. In the mesenteric lymph nodes, adenomegaly and microscopic lesions were mainly observed on day 6 pi. Parasite DNA was detected in 11% and 61.2% of the samples from mesenteric lymph nodes on days 3 and 6 pi, respectively, with higher parasite DNA detection rates and burdens in the medial and distal jejunal lymph nodes on day 6 pi. In the placentomes, on day 6 pi, gross lesions were not observed, although significant histological changes, such as endothelial activation and vascular thrombosis, were found in 18.6% and 8.3% of the placentomes, respectively. These findings lay the groundwork for future research aimed at elucidating the precise mechanisms underlying early abortions following T. gondii infection in pregnant sheep.
    Keywords:   Toxoplasma gondii ; early abortion; early infection dynamics; mesenteric lymph nodes; mid-gestation; placental thrombosis; sheep; small intestine
    DOI:  https://doi.org/10.1186/s13567-025-01557-1
  55. J Cell Sci. 2025 Jul 03. pii: jcs.263810. [Epub ahead of print]
    The adhesion plaque mediates fluid discharge and duplication of the contractile vacuole complex in Trypanosoma cruzi.
    Ingrid Augusto, Wendell Girard Dias, Alejandra Schoijet, Guillermo Daniel Alonso, Veronica Jimenez, Wanderley de Souza, Kildare Miranda.
      This work explores the intricate process of osmoregulation in Trypanosoma cruzi, the causative agent of Chagas disease, with a specific focus on the mechanisms of fluid discharge by the Contractile Vacuole Complex (CVC) and the role of the adhesion plaque (AP), a structure whose densities are located in the membrane domain shared by the CVC and the flagellar pocket. Cryopreparation of T. cruzi samples, combined with volume electron microscopy techniques, allowed for a comprehensive analysis of the essential mechanisms underlying the structural changes that take place in the AP during osmotic stress. Remodeling of the AP coupled to membrane fusion events leads to the formation of pores that connect the flagellar pocket and the CVC. The fluid discharge process followed sequential steps of pore opening, expansion, and closure, to allow membrane fusion. Additionally, this study uncovers structural variations in the CVC during cellular replication, providing insights into the cellular biology and physiology of trypanosomatids.
    Keywords:   Trypanosoma cruzi ; Adhesion plaque; Contractile vacuole; Fusion pore; Osmoregulation
    DOI:  https://doi.org/10.1242/jcs.263810
  56. Curr Drug Targets. 2025 Jun 24.
    Lipidomics in Breast Cancer: Decoding Metabolic Reprogramming and Unlocking Therapeutic Opportunities.
    Harshita Singhai, Sunny Rathee, Umesh K Patil.
      Lipidomics, a cutting-edge branch of metabolomics, provides a comprehensive understanding of the lipidome and its alterations in cellular and systemic processes. In breast cancer, a highly heterogeneous disease, lipidomics has emerged as a pivotal tool for exploring metabolic reprogramming, tumor progression, and therapeutic resistance. This review highlights the intricate relationship between lipid metabolism and breast cancer, with a focus on subtype-specific lipid dependencies, oxidative stress, and ferroptosis. Technological advancements, such as mass spectrometry and chromatography, have enabled precise profiling of lipid alterations, revealing distinct lipid signatures across breast cancer subtypes. Key enzymes like acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), along with lipid regulators like PPARγ, have been identified as central players in lipid-driven tumorigenesis. Lipidomic studies offer the potential for biomarker discovery and the development of lipid-targeted therapies. Despite challenges in standardization and integration with other omics approaches, lipidomics is poised to revolutionize breast cancer diagnostics and therapeutics, providing novel insights into the metabolic underpinnings of this complex disease.
    Keywords:  Lipidomics; biomarkers; breast cancer; ferroptosis; lipid metabolism; mass spectrometry; metabolic reprogramming.
    DOI:  https://doi.org/10.2174/0113894501387287250611095023
  57. Nat Commun. 2025 Jul 01. 16(1): 5554
    Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development.
    Nioosha Nekooie Marnany, Alwyn Dady, Isabelle Duband-Goulet, Frédéric Relaix, Roberto Motterlini, Roberta Foresti, Sylvie Dufour, Jean-Loup Duband.
      Metabolic reprograming has been linked to epithelial-to-mesenchymal transition (EMT) in cancer cells, but how it influences EMT in normal cells remains largely unknown. Here we explored how metabolism impacts delamination and migration of avian trunk neural crest cells, an important progenitor cell population of the vertebrate embryo. We report that delamination exhibits a quiescent metabolic phenotype whereas migration is characterized by OXPHOS-driven metabolism coupled to distinct expression of metabolic, EMT and developmental genes. While glucose and glutamine are required for delamination and migration, we uncover a specific role for glutamine and its catabolizing enzyme glutaminase in the unfolding of NCC delamination. Namely, glutamine is required for nuclear accumulation of glutaminase, which interacts and cooperates with Wnt signaling to regulate EMT gene expression and cell cycle during delamination. Our data indicate that similarly to cancer cells, embryonic cells engage metabolic enzymes for non-canonical signaling functions to connect metabolism with EMT.
    DOI:  https://doi.org/10.1038/s41467-025-58573-0
  58. bioRxiv. 2025 Jul 02. pii: 2025.07.02.662767. [Epub ahead of print]
    KMT2C and KMT2D regulate skeletal development through stage-specific epigenetic control of chondrogenesis.
    Gabrielle Quickstad, Dimitrios V Bikas, Sara Vardabasso, Karl B Shpargel.
      Many craniofacial disorders linked to mutations in enhancer-associated chromatin-modifying enzymes, including Kabuki syndrome (KS), present with a wide range of skeletal abnormalities. KS is a craniofacial development disorder characterized by mutations in KMT2D, a histone H3 lysine 4 (H3K4) methyltransferase. The KMT2D cellular origins and molecular pathways leading to skeletal deficits in KS are not well characterized. We previously demonstrated that KMT2D deletion in mouse cranial neural crest cells (cNCCs), the multipotent stem cells that contribute to many craniofacial structures, specifically impairs chondrocyte hypertrophic differentiation. Although we observed defects in cNCC endochondral ossification, broader skeletal function of KMT2D is largely unknown and its functional redundancy in skeletal development with its paralog, KMT2C, is understudied. We now find that KMT2D mutation within chondrocyte lineages results in postnatal growth defects and impaired skeletal bone development. We demonstrate redundancy of KMT2C in regulating endochondral ossification as mice lacking both methylases within chondrocyte lineages demonstrate severe deficits in bone formation. These methylases regulate change in chondrocyte state as hypertrophic differentiation is impaired with loss of both KMT2C and KMT2D. When both methylases are deleted in stem cell lineages, KMT2C/KMT2D double mutant cNCCs are unable to properly induce chondrocyte factors downstream of SOX9 activation. At the molecular level, there is a loss of H3K4me1 at de novo chondrocyte enhancers essential for skeletal development and an associated reduction in the efficiency of acetylation with KMT2C/D deficiency, suggesting partial dependency on KMT2C/D presence for appropriate deposition of H3K27ac. We propose a role for KMT2C and KMT2D in facilitating proper activation of genes downstream of SOX9 and RUNX2 transcription factors. Thus, we delineate a regulatory cascade orchestrated by chromatin-level modifications wherein KMT2C/D activity ensures commitment of chondrocyte lineages via enhancer priming. This work not only expands the functional repertoire of COMPASS family members but also defines a chromatin-based mechanism for vertebrate skeletal development, offering insights into the epigenetic basis of skeletal dysplasia and related congenital disorders.
    DOI:  https://doi.org/10.1101/2025.07.02.662767
  59. Eur J Med Res. 2025 Jul 03. 30(1): 567
    MLN0905 effectively kills gemcitabine-resistant pancreatic cancer cells by targeting PLK1.
    Min Lin, YongSha Pan, Shanshan Han, Lifei Zhu, Peng Ye, Ming Ye, Zejun Fang.
       BACKGROUND: Polo-like kinase 1 (PLK1) functionally mediates tumorigenesis of pancreatic cancer (PC) and associates with its drug resistance to gemcitabine, but related inhibitor therapies were poorly explored. MLN0905 is a novel small molecule inhibitor targeting PLK1. Here we investigate the therapeutic capacity for gemcitabine-resistant pancreatic cancer and related molecular mechanism of MLN0905.
    METHODS: The inhibitory efficacy of MLN0905 on gemcitabine-resistant PC cell lines was assessed using cell viability assays, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), the colony formation assay, and flow cytometry detecting cell cycle or apoptosis. In addition, changes in the G2/M phase ratio were further analyzed. Cell cycle and apoptosis-related defects in MLN0905 treated PC cells were detected using western blot analysis. In addition, a subcutaneous tumor model of pancreatic cancer (PC) resistant to gemcitabine was established in vivo to investigate the inhibitory effect of MLN0905 in animal model and evaluate its safety to liver or kidney functions. Tumor volume, tumor weight, Ki67 expression, and the expression of cluster of differentiation 31 (CD31) were measured following the administration of MLN0905. Meanwhile, several detects for alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU) and creatinine (Cr) were also performed to further confirm the safety of MLN0905 in liver and kidney functions.
    RESULTS: Experiments related to cell viability demonstrated that MLN0905 inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis in gemcitabine-resistant PC cell lines. Mechanistically, the phosphorylation level of PLK1 gradually deceased with the increase of drug concentration, while the expression of PHH3 and γH2A.x increased. In vivo evaluation showed the effective inhibition of MLN0905 in tumor growth and its good security.
    CONCLUSIONS: Our research has indicated that MLN0905 interferes with cancer cell DNA replication by specifically targeting PLK1, leading to cell cycle arrest and apoptosis, thereby preventing tumor growth and effectively eradicating gemcitabine-resistant pancreatic cancer cells, demonstrating satisfactory safety in this study. This research provides a detailed analysis of the interactions between MLN0905, PLK1, and gemcitabine resistance in the progression of pancreatic cancer, offering new prospects and insights for overcoming gemcitabine resistance in pancreatic cancer.
    Keywords:  Gemcitabine-resistant; MLN0905; PLK1; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s40001-025-02825-8
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