bims-toxgon 2026-07-05 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2026–07–05
nineteen papers selected by
Lakesh Kumar, BITS Pilani

Anticancer proteasome inhibitors are detrimental to the growth of Toxoplasma gondii in vitro.
Inheritance of four-membrane-bound structures in the "apicoplast-minus" Plasmodium falciparum.
Identification of UCB-9721 as a potent inhibitor of MyoA, the essential class XIV myosin motor of apicomplexan parasites.
Cysteine-S-nitrosylation inhibits ROP5-mediated immune evasion in Toxoplasma gondii.
Cyclic AMP compartmentalization drives signal specificity to control vector colonization and mammalian host infection by American trypanosomes.
Lysine pyruvylation couples glycolytic flux to epigenetic regulation.
Mechanism-based inhibition of zinc-dependent histone deacetylases.
Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
PfApiAT2 is a proline transporter essential for the transmission of Plasmodium falciparum by the mosquito vector.
Structural basis for host membrane binding and remodeling by invading malaria parasites.
Study of Class I HDAC-1, -2, and -3 Inhibitors Designed by Bioisosteric Replacement of Zinc Binding Groups and Caps of Traditional Pan Inhibitors: An In Silico Approach.
Mechanisms influencing transient cytoplasmic protein targeting to intracellular lipid droplets.
Epigenetic Regulations by Olive Bioactives: Targeting HDAC for Disease Prevention and Therapy.
Glucose and Glutamine Define Independent Activation-Braking Metabolic States in Triple Negative Breast Cancer Cells.
A temporal phospho-acetylome atlas of human myogenesis identifies coordinated post-translational regulation.
Integrated lipidomic and transcriptomic profiling of the host response in human malaria.
Post-translational modifications in triple-negative breast cancer: research status and translation challenges.
The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.
Kat5 deficiency in alveolar type II cells licenses STAT6-driven glycolytic reprogramming and pulmonary fibrosis.

BMC Res Notes. 2026 Jun 29.

Anticancer proteasome inhibitors are detrimental to the growth of Toxoplasma gondii in vitro.

Meir Zhang, Pascale S Guiton.

   OBJECTIVE: Toxoplasma gondii is a globally widespread intracellular protozoan that infects an estimated 25% of the world's human population. There is currently no cure for chronic toxoplasmosis, and treatments for acute infection often cause harmful side effects. Here, we used well-established growth assays to evaluate the anti-toxoplasmic effects of three FDA-approved anticancer proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, on Toxoplasma growth in vitro.
RESULTS: We found that treatment of Toxoplasma with bortezomib, carfilzomib, and ixazomib inhibits parasite growth with IC50 values of 204.9 nM, 116.5 nM, and 7.05 µM, respectively. Additionally, bortezomib and ixazomib impair parasite replication 24 h post-infection and cause asynchronous cell division and the formation of aberrant parasites. Our study provides evidence in favor of further investigation of these anticancer drugs for in vivo efficacy and their repurposing for the treatment of toxoplasmosis.

Keywords:   Toxoplasma gondii ; Anticancer drugs; Proteasome inhibitors

DOI:  https://doi.org/10.1186/s13104-026-07930-3
mSphere. 2026 Jun 29. e0002426

Inheritance of four-membrane-bound structures in the "apicoplast-minus" Plasmodium falciparum.

Wei Xu, Ikechukwu Nwankwo, Sean T Prigge, Hangjun Ke.

  Most apicomplexan parasites contain a plastid-derived organelle called the apicoplast, which originated through secondary endosymbiosis. As a result of this evolutionary trajectory, the non-photosynthetic apicoplast is surrounded by four membranes and contains many bacterial-like, druggable targets. It is widely accepted that asexual malaria parasites (Plasmodium falciparum) can thrive under antibiotic treatment if supplemented with high concentrations of isopentenyl pyrophosphate (IPP, 200 µM), and these IPP-rescued parasites are thought to lack the apicoplast and its 35 kb genome but possess many vesicles. However, our findings suggest that this "apicoplast-minus" concept may warrant reconsideration. Using live-cell microscopy, we observed that apicoplast-derived vesicles closely colocalize with mitochondria in late schizonts and are faithfully segregated into merozoites during schizogony, suggesting that these vesicles are inherited from the previous cycle rather than newly synthesized. Furthermore, immuno-electron microscopy (immuno-EM) revealed that the apicoplast-minus parasites possess structures surrounded by four membranes, in addition to single-membrane-surrounded entities. The presence of four-membrane-bound structures suggests that the apicoplast has not truly disappeared in the apicoplast-minus P. falciparum but has remained in a distinct, diminished form. We propose that these distinct four-membrane-bound structures still retain essential biochemical and/or structural functions, which act as barriers to the complete loss of apicoplast when the parasites face antibiotic stress and IPP rescue.
IMPORTANCE: The plant-like organelle named apicoplast is essential for malaria parasites and is a major antimalarial drug target. For more than a decade, scientists have believed that malaria parasites in the blood stages could dispense with the apicoplast if they were supplied with a critical metabolite made by the organelle, leading to the idea of "apicoplast-minus" parasites. Our results challenge this long-standing view. We find that even when the apicoplast is disrupted, the organelle remains in a highly reduced form. This apicoplast-derived organelle is inherited as parasites continue their life cycles, suggesting that it contains essential functions even when the organelle is disrupted. Our data reveal an unexpected level of complexity in apicoplast biology and open new doors for future identification of essential apicoplast-derived pathways that cannot be easily bypassed.

Keywords:  Plasmodium falciparum; apicoplast; apicoplast derivative; malaria

DOI:  https://doi.org/10.1128/msphere.00024-26
bioRxiv. 2026 Jun 19. pii: 2026.06.18.733251. [Epub ahead of print]

Identification of UCB-9721 as a potent inhibitor of MyoA, the essential class XIV myosin motor of apicomplexan parasites.

Anne K Snyder, Filomena Tedesco, Anne Kelsen, Eddie Wehri, Binod Nepal, Jose Teixeira, Emmett Dews, Sachie Kanatani, Kyle Kasprzak, Jonathan Oliva, Kaesi Morelli, Samantha Beck Previs, Bruno Martorelli di Genova, Fran Sverdrup, Martin J Boulanger, Photini Sinnis, Christopher D Huston, Sandhya Kortagere, David M Warshaw, Julia Schaletzky, Nicholas J Westwood, Gary E Ward.

The virulence of Toxoplasma gondii and other apicomplexan parasites relies on a unique form of cellular motility driven by MyoA, an unconventional class XIV myosin motor protein. To identify new chemical probes for investigating the molecular mechanisms of parasite motility, we screened over 50,000 small molecules for inhibitors of T. gondii MyoA (TgMyoA). The top hit from the screen, UCB-9721, is almost 40-fold more potent as an inhibitor of TgMyoA actin-activated ATPase activity than the previously described TgMyoA inhibitor, KNX-002, and 45-fold more potent at inhibiting parasite motility, with no detectable toxicity towards mammalian cells. UCB-9721 also inhibited the motility and/or growth of the related apicomplexan parasites Plasmodium falciparum, Cryptosporidium parvum, and Babesia duncani, suggesting that this compound will be a useful new chemical probe for studying motility and MyoA function in apicomplexan parasites more broadly. While UCB-9721 and KNX-002 were identified independently, they share a similar chemical scaffold. To determine why UCB-9721 is so much more potent than KNX-002 and to inform future development of this inhibitor class, we undertook comparative molecular docking analyses, targeted TgMyoA mutagenesis, and a directed structure-activity relationship analysis. The results identified the sulfonamide group of UCB-9721 and its hydrogen bond interactions with R249, E275 and a stabilized water network within the TgMyoA binding pocket as key to the compound's increased potency. Further development of UCB-9721, informed by the results presented here, may transform this promising new chemical class into actionable drug development leads against this important group of human and animal pathogens.

DOI: https://doi.org/10.64898/2026.06.18.733251
mSphere. 2026 Jun 30. e0030926

Cysteine-S-nitrosylation inhibits ROP5-mediated immune evasion in Toxoplasma gondii.

S L Lempke, P DiMare, B Nichols, L F Fitzsimmons, A Chaudhry, V C Grebe, M L Reese, S E Ewald.

  Reactive nitrogen species (RNS) are a mechanism to control microbial infections conserved across the host species of the obligate intracellular parasite Toxoplasma gondii. Cysteine S-nitrosylation (SNO) is a reversible post-translational modification that controls complex cell behaviors by regulating protein interactions and signal transduction events. Here, we identified a cluster of T. gondii secreted effector proteins that are SNO-modified in a host inducible nitric oxide synthase (iNOS)-dependent manner. Among these were the rhoptry protein 5 (ROP5) paralogs, major virulence determinants in T. gondii and an immunodominant antigen in B6 mice. ROP5 was necessary for Type I and Type II parasites to evade IFN-γ-mediated immune clearance in iNOS-deficient macrophages. RNS led to the loss of ROP5 association with the parasitophorous vacuole membrane (PVM), which is necessary for the known functions of ROP5. Infection with ROP5 knockout parasites rescued the susceptibility of iNOS-deficient mice to infection with Type II T. gondii. Together, these data indicate that RNS can promote cell-autonomous parasite clearance by inhibiting the function of ROP5 alleles at the PVM.
IMPORTANCE: RNS are necessary for cell-autonomous immunity to T. gondii infection; however, the molecular mechanisms by which RNS regulate parasite control remain poorly understood. Our findings support a model in which post-translational modification of ROP5 by RNS is a conserved mechanism of inhibiting the functions of divergent ROP5 paralogs. These data provide a specific example of how host RNS are used to counter T. gondii immune evasion effectors that can be applied to understand how nitrosylation regulates the function of other parasite effectors and the role of RNS in the control of other intracellular pathogens.

Keywords:  RNS; Toxoplasma gondii; cell-autonomous immunity; iNOS; innate immunity; interferons; macrophages; nitric oxide synthase; nitrosylation

DOI:  https://doi.org/10.1128/msphere.00309-26
PLoS Pathog. 2026 Jun 29. 22(6): e1013784

Cyclic AMP compartmentalization drives signal specificity to control vector colonization and mammalian host infection by American trypanosomes.

Milad Ahmed, Joshua Carlson, Asima Das, Syeda Farjana Hoque, Joshua B Benoit, Miguel A Chiurillo, Noelia Lander.

Cyclic AMP (cAMP) signaling is crucial for environmental sensing and response to stress conditions in trypanosomatids. However, the mechanisms driving the specificity of cAMP signals remain poorly understood in these protozoan parasites. We recently identified two putative cAMP microdomains in Trypanosoma cruzi, the causative agent of Chagas disease. Here, considering the localization of three phosphodiesterases, PDEC at the contractile vacuole complex (CVC), and PDEB1 and PDEB2 along the flagellum, we modulated their expression to functionally characterize the flagellar tip (FT) and the CVC as individual PDE-defined cAMP signaling compartments, named FT-cAMP and CVC-cAMP, respectively. We generated PDE knockout and overexpression cell lines to selectively alter cAMP signals generated in each compartment. Our results indicate that FT-cAMP mediates cell adhesion, metacyclogenesis, host cell invasion, and intracellular replication, while CVC-cAMP is important for osmoregulation and epimastigote proliferation. In addition, ablation of flagellar PDEB1 and PDEB2 enhanced the parasite's ability to colonize the hindgut of the triatomine vector, whereas PDEC-KO parasites were impaired in their establishment in the insect's hindgut. The observed phenotypes were PDE-specific, demonstrating functional segregation between the two compartments. Our data provide robust evidence on the presence of compartmentalized cAMP signals in T. cruzi, linking the role of PDE-defined cAMP pools to specific cellular responses during the parasite's life cycle.

DOI: https://doi.org/10.1371/journal.ppat.1013784
Nat Metab. 2026 Jul 03.

Lysine pyruvylation couples glycolytic flux to epigenetic regulation.

Xiaohan Song, Panpan Peng, Haonan Zheng, Yanan Zheng, Qianjing Wang, Yu Ge, Doudou Tan, Lu Chen, Xinbo Wang, He Huang.

Post-translational modifications (PTMs) dynamically regulate protein function, with metabolite-driven PTMs linking metabolism to protein regulation1,2. We have previously discovered lysine lactylation, showing that lactate can directly modify proteins and influence cancer progression3,4. Recently, pyruvate, another glycolytic metabolite, was shown to directly modify STAT1 at lysine 201, thereby suppressing type I interferon signalling5. Yet, the enzyme governing this modification, its substrate landscape and potential roles beyond innate immunity remain entirely unexplored. Here we report the systematic characterization of lysine pyruvylation (Kpy). Through biochemical and proteomic approaches, we establish the widespread existence of this modification, identifying 88 Kpy sites in mammalian cells. We investigate the dynamic regulation of Kpy upon metabolic perturbations and find that Kpy fluctuates with changes in glycolytic flux and pyruvate levels. Furthermore, we identify sirtuin 3 (SIRT3) as responsible for removing Kpy, while histone acetyltransferase 1 (HAT1) and p300 (EP300) catalyse its addition. Finally, we explore the function of Kpy in transcriptional regulation. Overall, Kpy expands the repertoire of metabolite-driven PTMs and provides insights into how pyruvate directly modulates protein function.

DOI: https://doi.org/10.1038/s42255-026-01556-2
RSC Chem Biol. 2026 Jul 01.

Mechanism-based inhibition of zinc-dependent histone deacetylases.

David W Christianson.

The hallmark of a mechanism-based inhibitor is a chemical transformation that occurs upon binding in an enzyme active site that typically yields a more potent inhibitory species. A mechanism-based enzyme inhibitor can be a closely-related analogue of the native substrate, or it can be strikingly different in its structure. Here, the discovery of mechanism-based inhibitors is briefly reviewed to establish a foundation for understanding the mechanism-based inhibition of zinc-dependent histone deacetylases (HDACs), enzymes that play critical roles in epigenetics and the regulation of myriad cellular processes. Notably, the discovery of mechanism-based HDAC inhibition was an unexpected surprise emanating from X-ray crystal structures of enzyme-inhibitor complexes. In each example discussed, the C[double bond, length as m-dash]O, C[double bond, length as m-dash]N, or C[triple bond, length as m-dash]N group of an inhibitor undergoes nucleophilic attack by zinc-bound water in the same manner as the C[double bond, length as m-dash]O group of the native HDAC substrate; however, nucleophilic attack at the bound inhibitor leads to the formation of a tightly-bound enzyme-inhibitor complex. The dual requirements of steric fit as well as fitness for chemical activation can be exploited in unique strategies to enhance inhibitory potency and selectivity.

DOI: https://doi.org/10.1039/d6cb00150e
Nat Commun. 2026 Jul 01.

Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.

Abhisha Sawant Dessai, Nadya A Elhalawany, Tao Dai, Justine J Jacobi, Christian Prechtl, Alphonse N Dimeck, Sierra R Morton, Mark D Long, Prashant K Singh, Nagireddy Putluri, Mariana Lopes, Song Liu, Dominic J Smiraglia, Katerina V Gurova, Peder J Lund, Leah A Gates, Sung Yun Jung, Subhamoy Dasgupta.

Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. Here we show, a metabolic pathway in the nucleus controls acetylation of histones by nuclear localization of mitochondrial enzymes aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies show that IDH2 and ACO2 catalyze reductive carboxylation of α-ketoglutarate to rapidly synthesize citrate to increase nuclear acetyl-CoA pool. Genetic and proteomic analyses reveal nuclear IDH2 and ACO2 form a complex with KAT2A/GCN5 for acetylation of histones to increase chromatin accessibility and activation of proliferative genes. Robust nuclear expressions of ACO2 and IDH2 drive aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work reveals a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors.

DOI: https://doi.org/10.1038/s41467-026-74786-3
Nat Commun. 2026 Jul 03.

PfApiAT2 is a proline transporter essential for the transmission of Plasmodium falciparum by the mosquito vector.

Malhar Khushu, R Charles Kissel, Jamie Kauffman, Claudia Taccheri, Naresh Singh, Robert L Summers, Leigh D Plant, Dyann F Wirth, Flaminia Catteruccia, Selina Bopp.

Plasmodium falciparum oocysts undergo an explosive biomass increase during development in Anopheles mosquitoes, a dramatic growth process likely promoted by as-yet unknown nutrients scavenged from the mosquito. We previously observed in blood-stage parasites, that the amino acid transporter PfApiAT2, although dispensable, regulates proline homeostasis and mediates resistance to halofuginone, a potent proline-tRNA synthetase inhibitor. Here, we demonstrate that PfApiAT2 is a proline-specific transporter essential for early oocyst development in Anopheles gambiae. Halofuginone-resistant pfapiat2-mutant parasites form stunted oocysts severely defective in sporozoite production. This phenotype is recapitulated in PfApiAT2-knockout parasites that undergo a complete block in sporogony, forming oocysts that stall and degenerate. Remarkably, this growth defect can be rescued by nutrient supplementation to the mosquito vector. By identifying an amino acid transporter essential for oocyst growth, our data unveil a vulnerability in P. falciparum transmission, revealing a critical nutritional dependency of the parasite on its mosquito vector.

DOI: https://doi.org/10.1038/s41467-026-75126-1
Cell. 2026 Jun 30. pii: S0092-8674(26)00699-9. [Epub ahead of print]

Structural basis for host membrane binding and remodeling by invading malaria parasites.

Meseret T Haile, Daphne A Kaxiras, James Zhen, Carolyn L Lee, Britney Jiang, Jennifer L Small-Saunders, Chi-Min Ho.

  The Plasmodium moving junction is central to malarial host-cell invasion, and yet its function remains unclear. Here, we determine the endogenous structure of the basic repeating unit of the moving junction, purified directly from invasion-stalled Plasmodium falciparum parasites, revealing a sailboat-shaped 1:1:1:1 assembly of apical membrane antigen 1 (PfAMA1) and rhoptry neck proteins 2, 4, and 5 (PfRON2, PfRON4, and PfRON5). We observe two PfRON2 transmembrane helices that anchor the complex in the red blood cell (RBC) membrane and display an extracellular handle for PfAMA1 binding. PfAMA1 directly contacts the RBC membrane, strengthening the connection. PfRON2/4/5 form a large, basic platform inside the RBC that electrostatically engages the RBC membrane and wedges seven amphipathic helices deep into the bilayer, suggesting an active role in host-membrane remodeling. We then leverage the native membrane context revealed by our structure, along with recent advances in computational protein design, to enable the rational design of a small protein binder that inhibits invasion.

Keywords:  BindCraft; cryo-EM; endogenous structural biology; host-parasite; invasion; malaria; membrane remodeling; protein binders; protein design; vaccine target

DOI:  https://doi.org/10.1016/j.cell.2026.06.012
Curr HIV Res. 2026 ;24(1): 17-42

Study of Class I HDAC-1, -2, and -3 Inhibitors Designed by Bioisosteric Replacement of Zinc Binding Groups and Caps of Traditional Pan Inhibitors: An In Silico Approach.

Simon Mugisa, Hayiru Mohammed, Ercan Bursal, Manikanta Murahari.

   INTRODUCTION: Despite the significant contribution of Antiretroviral Therapy (ART) in the management of viral replication and infection, HIV latency still presents a major barrier to complete eradication. Histone Deacetylases (HDACs), particularly Class I HDACs (the isoforms 1, 2 and 3) have been reported to play a pivotal role in maintaining this latency by contributing to transcriptional silencing. Selective HDAC inhibitors (HDACis) that target these isoforms can reactivate HIV reservoirs, encouraging viral growth and its subsequent recognition by the immune system, thus its clearance from the body. This is known as the "shock and kill" hypothesis.
METHODS: We employed computational methods to design novel HDACis by replacing the Zinc Binding Groups (ZBGs) and caps of known pan-HDAC inhibitors with respective bioisosteric fragments. Ligand design was based on modifying the structures of Vorinostat, Belinostat, Etinostat, and Givinostat by retaining their linkers while substituting caps and ZBGs. Molecular docking with Biovia (Discovery Studio) was performed to evaluate the binding affinity against the three target proteins (HDAC1, HDAC2, and HDAC3). The top-performing ligands underwent Molecular Dynamics (MD) simulations using GROMACS and binding energy calculations by the MMPBSA method to assess the stability of the complexes. Furthermore, ADMET screening was performed for drug-likeness evaluation and toxicity predictions.
RESULTS: Among the sixteen designed ligands, Hdi2 and Hdi10 emerged as the top performers, showing the highest binding affinities. Hdi2 demonstrated exceptionally high scores (-92.20, - 80.00, and -74.31 Kcal/mol with HDAC1, HDAC2, and HDAC3, respectively). Hdi10, on the other hand, demonstrated consistent stability across all isoforms. MD simulations revealed high stability for Hdi10 with HDAC2 and HDAC3 and for Hdi2 with HDAC1, as suggested by low values of RMSD, RMSF, and robust hydrogen bonding. MMPBSA analysis revealed strong complex stability with up to -51.7 kJ/mol predicted binding energies. ADMET prediction showed negligible toxicity (LD50: 1600 mg/kg and 6000 mg/kg for Hdi2 and Hdi10, respectively) and zero Lipinski violations.
DISCUSSION: These findings indicate the potential of Hdi2 and Hdi10 as selective and stable binders of Class I HDAC isoforms, addressing the limitations of existing pan-HDAC inhibitors explored in HIV latency reversal studies. The observed favorable docking, stability, and safety profiles highlight the prospects for further exploration of these compounds as more effective and less toxic LRAs. Nevertheless, the results of this study were solely computational predictions and therefore require experimental validation to confirm the biological efficacy and isoform selectivity of the studied ligands.
CONCLUSION: This study identified two promising novel HDAC inhibitors, Hdi2 and Hdi10, for further experimental investigation and optimization as potential LRAs for HIV latency reversal. These findings support the rational design of selective HDACis using computational approaches as efficient and cost-effective methods for the identification of future LRAs.

Keywords:  Histone deacetylase; bio-isosteric replacement; kill; latency; pan inhibitors; shock; zinc binding

DOI:  https://doi.org/10.2174/011570162X379088251002114150
Biochem Soc Trans. 2026 Jul 29. 54(7): 873-885

Mechanisms influencing transient cytoplasmic protein targeting to intracellular lipid droplets.

Jay L Laws, Ebony A Monson, Lachlan A Wallace, Karla J Helbig, Cameron J Reddington.

  Lipid droplets (LDs) have a multitude of functions ranging from lipid storage to fighting infection and are decorated with a variety of proteins on their surface that determine their functions and behaviours. Mass spectrometric analysis has identified the vast array of LD-localised proteins, which have recently been shown to be dynamic, changing in response to cellular stress, infection, and altered homeostasis. Here, we review the key mechanisms of cytoplasmic protein interactions with the LD, highlighting conventional features like amphipathic helices, atypical sequence-based motifs, protein-protein interactions, and post-translational modifications that confer dynamic targeting of proteins to the surface of the LD. A better understanding of the transient LD proteome and the mechanisms that confer LD protein targeting will allow researchers to develop a more thorough understanding of LD biology, and the role of LDs in cellular homeostasis and disease.

Keywords:  CYTOLD; Lipid droplets; Membrane targeting; Post-translational modifications

DOI:  https://doi.org/10.1042/BST20250461
Curr Nutr Rep. 2026 Jun 29. pii: 57. [Epub ahead of print]15(1):

Epigenetic Regulations by Olive Bioactives: Targeting HDAC for Disease Prevention and Therapy.

Mousumi Debnath, Soumya Sharma, Siddhi Joshi, Dikshita Aneja.

   PURPOSE OF THIS REVIEW: The objective is to understand the bioactive compounds present in olive as functional natural histone deacetylase (HDAC) inhibitors and epigenetic modulators. This review focusses on oleuropein, hydroxytyrosol, and oleanolic acid analyzing their molecular targets, signaling pathways in major non communicable diseases. By integrating evidences from studies in cell lines, animals and preclinical studies, this review aims to identify research gaps, clarify mechanistic inconsistencies and propose future translational strategies for leveraging olive bioactives in precision epigenetic therapy.
RECENT FINDINGS: Oleuropein, hydroxytyrosol, and oleanolic acid exhibit epigenetic regulatory potential through modulation of HDAC activity. Oleuropein has been reported to promote histone acetylation leading to tumor suppressor genes and modulation of apoptosis signaling pathways. Whereas hydroxytyrosol exerts epigenetic effects by attenuating HDAC expression and oxidative stress mediated chromatin remodeling thereby influencing inflammatory metabolic gene regulation. Oleanolic acid demonstrates HDAC inhibitory potential and modulates acetylation dependent transcriptional pathways involved in cell cycle regulation, inflammation and cancer progression. Collectively they may serve as adjunct epigenetic modulators pending further validations. This review offers insights into the potential of oleuropein, hydroxytyrosol, and oleanolic acid as HDAC targeting agents for addressing metabolic disorders, cardiovascular protection, cancer prevention, and neurodegenerative disease therapy. These compounds also regulate glucose metabolism and glucose sensitivity, addressing metabolic disorders. They show encouraging preclinical evidence like HDAC inhibitors.

Keywords:  Anti-inflammatory; Disease prevention; Epigenetic modulation; Histone deacetylase inhibitors; Olive; Preventive medicine

DOI:  https://doi.org/10.1007/s13668-026-00779-9
Cancer Genomics Proteomics. 2026 Jul-Aug;23(4):23(4): 629-648

Glucose and Glutamine Define Independent Activation-Braking Metabolic States in Triple Negative Breast Cancer Cells.

Elizabeth A Mazzio, Renee Reams, Ramesh B Badisa, Jean Baptiste Lamango, Zonelle Hanley, Karam F A Soliman.

   BACKGROUND/AIM: Cancer metabolism is often viewed as a cooperative reliance on glucose and glutamine; however, whether these nutrients can enforce discrete, non-overlapping metabolic states remains unclear. This study aimed to isolate nutrient-specific regulatory programs.
MATERIALS AND METHODS: MDA-MB-231 human breast cancer cells were cultured under four distinct metabolic environments: glucose/glutamine nutrient-repleted (fed), dual glucose/glutamine deficiency, and isolated repletion of either glucose or glutamine. Groups were evaluated for integrated transcriptomic, metabolomic, and lipidomic profiles to identify only the non-redundant, nutrient-enforced architectures.
RESULTS: The data show a mutually restrictive mechanistic state. Glutamine functions as a metabolic architect, restoring glycolytic enzyme transcripts (without lactate production), while inducing PDK1/3 which would decouple glycolysis from the TCA cycle. These changes are concomitant with a glutamine flux toward reductive TCA-driven lipogenesis, citric acid overflow, sterol synthesis (SREBF1/2), structural membrane expansion (phospholipids/sphingolipids) and the unique production of alanine as a nitrogen pool, independent of glycolytic flux. Conversely, glucose alone acts as the executor, licensing chromatin engagement, DNA replication, and mitotic progression. Glucose alone resolved ER stress, restored hexose-phosphate-derived glycosylation (mannose-6-phosphate), enabled lactic acid production, and diverted excess carbon into a triglyceride storage pool (>40% of lipids). Notably, each nutrient suppressed core elements of the other's program, revealing a reciprocal activation-braking system. Interestingly, ATP yield from glucose or glutamine alone were comparable, but not arbitrary; instead, aligned with the functional state of the cell. Glucose alone supported glycolytic phosphorylation and proliferative execution, as marked by lactate accumulation, whereas glutamine alone supported Krebs cycle-related phosphorylation, characterized by citrate accumulation and the maintenance of cellular structure and membrane infrastructure.
CONCLUSION: Glucose and glutamine enforce a balance of two independent, reciprocally regulated metabolic states. This data provides a systems-level explanation for metabolic resilience in cancer and may lead to the identification of nutrient-specific targets for combination therapy.

Keywords:  Cancer metabolism; ER stress; PDK; Warburg effect; anaplerosis; breast cancer; glucose–glutamine reciprocity; glutaminolysis; lipid remodeling; metabolic plasticity; nutrient-enforced metabolic states; oxidative phosphorylation; pyruvate dehydrogenase kinase; substrate-level phosphorylation; transcriptional state control

DOI:  https://doi.org/10.21873/cgp.20593
Mol Cell Proteomics. 2026 Jul 02. pii: S1535-9476(26)00115-5. [Epub ahead of print] 101619

A temporal phospho-acetylome atlas of human myogenesis identifies coordinated post-translational regulation.

Lauren E Smith, Christina E Hagensen, Vasileios Tsiamis, Ashley J van Waardenberg, Kamel Mamchaoui, Ole N Jensen, Veit Schwämmle, Adelina Rogowska-Wrzesinska.

  Skeletal muscle differentiation depends on precise temporal regulation of protein modifications. To define how phosphorylation and lysine acetylation change during this process, we applied tandem mass tag (TMT)-based quantitative proteomics to human myoblasts sampled at six stages spanning proliferation, induction of differentiation, and early myotube formation. Using sequential enrichment of phosphorylated and acetylated peptides, high-pH fractionation, and high-resolution mass spectrometry, we identified more than 22,000 modified peptides and quantified their temporal behavior after correction for protein abundance. Phosphorylation exhibited extensive site-specific remodeling throughout the time course, whereas acetylation showed a pronounced relative increase during late differentiation. Integration of corrected modification levels with protein abundances and temporal clustering revealed stage-specific regulation of processes linked to cell-cycle withdrawal, metabolic transitions, cytoskeletal reorganization, and chromatin-associated functions. Predicted temporal activity profiles of kinases, acetyltransferases, and deacetylases uncovered coordinated regulatory patterns, including activity relationships involving CK2A1-HDAC1/2, PRKAA1-HAT1, and CDK1/2-KAT7. Dual-modified proteins such as lamin A/C and glycolytic enzymes displayed densely regulated clusters of phosphorylation and acetylation sites that may contribute to nuclear remodeling and metabolic adaptation during myogenesis. Together, this work provides a high-resolution temporal phospho-acetylome atlas of human muscle cell differentiation, identifies candidate phosphorylation-acetylation coordination patterns, and establishes a systems-level resource for future mechanistic studies of post-translational regulation in skeletal muscle development.

Keywords:  GAPDH; Skeletal muscle differentiation; kinase activity prediction; lamin A/C; lysine acetylation; phosphorylation; post-translational modification crosstalk; quantitative proteomics

DOI:  https://doi.org/10.1016/j.mcpro.2026.101619
Genome Biol. 2026 Jun 30.

Integrated lipidomic and transcriptomic profiling of the host response in human malaria.

Wael Abdrabou, Dariga Bolatbay, Issiaka Soulama, Maria Nikulkova, Mame Massar Dieng, Saruul Zorigt, Manar Alshaikh, Samuel Sindié Sermé, Salif Sombié, Noelie Bere Henry, Désiré Kargougou, Sam Aboubacar Coulibaly, Vinu Manikandan, Aïssatou Diawara, Jane M Carlton, Youssef Idaghdour.

   BACKGROUND: Identifying the mechanisms of host-parasite interactions in vivo in malaria is essential for the development of antimalarial strategies tailored to clinically and physiologically relevant contexts.
RESULTS: We analyzed 396 paired global serum lipidomes from pediatric patients sampled before and during blood-stage malaria infection in Burkina Faso, spanning three ethnic groups (Gouin, Mossi, and Fulani). Consistent infection-induced remodeling of the host lipidome was identified across populations, including depletion of 47 host-derived lipid species that correlated with parasitemia. Notably, we observed that Plasmodium falciparum selectively scavenges linoleic acid-containing phospholipids to support its proliferation and validated this with parasite culture assays. This integrative multi-omics analysis combining lipidomic profiles with host-parasite transcriptomes further identified a Plasmodium falciparum transcriptional program associated with lipid turnover in vivo.
CONCLUSIONS: These results provide a high-resolution profile of lipidomic perturbations in malarial children and demonstrate how integrated clinical phenotyping, cross-ethnic population sampling, and multi-omics can reveal key host-parasite interactions and clinically relevant metabolic changes within the human host.

Keywords:  Ethnicity; High resolution lipidomics; Host-parasite interactions; Linoleic acid; Malaria; Metabolomics; Phospholipids

DOI:  https://doi.org/10.1186/s13059-026-04180-1
Cell Signal. 2026 Jun 27. pii: S0898-6568(26)00351-7. [Epub ahead of print]146 112696

Post-translational modifications in triple-negative breast cancer: research status and translation challenges.

Jia-Mei Wang, Yi Zhou, Fei Li, Yu Ding.

  Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 amplification. The lack of therapeutic targets contributes to its poor prognosis and limited treatment options. Nowadays, there is growing evidence that post-translational modifications (PTMs) play important roles in shaping the aggressive nature, immune microenvironment, and metabolic pathways in many tumor types. Here, in this review, we comprehensively summarized the roles of key PTMs, including phosphorylation, ubiquitination, acetylation, protein methylation, SUMOylation, lactylation, glycosylation, β-hydroxybutyrylation, and succinylation in TNBC. We discussed detection technologies for each PTM, detailed their molecular mechanisms and biological functions, and suggested therapeutic strategies targeting these modifications. Moreover, we reviewed PTM crosstalk networks and their clinical implications. Finally, we discussed the translational challenges and propose solutions for developing PTM-based diagnostics and therapies for TNBC. An evidence stratification framework was applied to grade the strength of the reviewed findings, distinguishing mechanistically validated, correlative, and clinically actionable evidence.

Keywords:  Biomarkers; Molecular mechanism; Post-translational modifications; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.cellsig.2026.112696
Oncogene. 2026 Jul 03.

The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.

Xiaozhen Yang, Shuming Wang, Yuzhong Yang, Aiyu Ma, Zhiyi Chen, Xuemei Zhang, Yan Zhang, Jinhua Zheng, Xiang Zheng.

N6-methyladenosine (m6A) is one of the most important RNA modifications and is widely distributed across mRNAs and non-coding RNAs. Its deposition, removal, and recognition are dynamically regulated by a set of proteins, including methyltransferases (writers), demethylases (erasers), and binding proteins (readers). Through these regulators, m6A modifications influence key aspects of RNA metabolism, including stability, splicing, nuclear export, and translation efficiency, dynamically regulating cell fate. Protein lactylation is a reversible post-translational modification occurring on lysine residues of both histones and non-histones, with lactate or lactyl-CoA serving as the substrate. Lactylation modulates protein properties, including structure, function, and activity, thereby influencing gene expression. RNA m6A modifications and protein lactylation significantly regulate the biological behaviors of tumors, including proliferation, invasion, metastasis, metabolic reprogramming, immune evasion and treatment resistance. In recent years, their crosstalk has garnered increasing attention. On one hand, m6A regulatory proteins can be regulated by lactylation, either directly or via histone lactylation-mediated epigenetic regulation. On the other hand, m6A modifications may promote protein lactylation by regulating glycolysis and lactate production. This bidirectional interaction forms a regulatory loop that influences tumor progression. This review summarizes the emerging role of the crosstalk between RNA m6A modification and protein lactylation in tumor progression.

DOI: https://doi.org/10.1038/s41388-026-03878-7
Nat Commun. 2026 Jul 03.

Kat5 deficiency in alveolar type II cells licenses STAT6-driven glycolytic reprogramming and pulmonary fibrosis.

Youjing Yang, Yi Ling, Jianzhong Li, Qianmin Li, Yanmei Feng, Jun Xiao, Yu Ma, Shasha Tao.

Pulmonary fibrosis (PF) remains a lethal progressive disease with poorly defined molecular drivers. Epithelial dysfunction and metabolic reprogramming contribute to PF, but the mechanistic link between these processes remains unclear. Here, we identify a Kat5-STAT6 epigenetic-metabolic axis that governs fibrotic progression. Kat5 directly acetylates STAT6 at lysine 636 (K636), thereby suppressing STAT6 dimerization, phosphorylation and nuclear translocation. In fibrotic lungs, STAT6 acetylation at K636 is reduced, leading to its hyperactivation. Activated STAT6 drives transcription of pro-glycolytic enzyme hexokinase 2 (HK2), promoting metabolic reprogramming in alveolar type II (ATII) cells and extracellular matrix deposition. ATII cell-specific restoration of Kat5 rescues STAT6 acetylation, normalizes its activity and ameliorates fibrosis in vivo. Mechanistically, Kat5-mediated STAT6 acetylation functions as a biochemical brake that limits cooperation with profibrotic mediators such as tissue plasminogen activator (tPA). These findings redefine STAT6 regulation, highlight an acetylation-phosphorylation checkpoint controlling fibrogenesis, and suggest that Kat5 enhancers or STAT6 acetylation mimetics may represent potential therapeutic strategies for chronic lung disease.

DOI: https://doi.org/10.1038/s41467-026-75317-w