bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2026–07–26
fifteen papers selected by
Lakesh Kumar, BITS Pilani
  1. Simulated Microgravity Reprograms Host Cell Architecture and Mitochondrial Function, Altering Toxoplasma gondii Growth.
  2. Phosphatidylinositol-4-phosphate signaling regulates dense granule biogenesis and maturation in Toxoplasma gondii.
  3. Expression of Concern: Molecular prevalence, phylogeny and hematological impact of Toxoplasma gondii and Plasmodium spp. in common quails from Punjab, Pakistan.
  4. Immunogenicity and Protective Efficacy of a Toxoplasma gondii Glycoprotein-Enriched Fraction in Mice.
  5. An Immunoinformatic Approach for a Multi-Epitope Vaccine Against Toxoplasma gondii.
  6. Divergent Autophagy Pathways in Plasmodium: Mechanisms, Functions, and Therapeutic Potential.
  7. Cyclic GMP-dependent activation of Ca2+ release from the ER and digestive vacuole at distinct phases of intraerythrocytic Plasmodium falciparum development.
  8. Antimalarial cytoskeletal targeting with broad apicomplexan activity.
  9. Hdac3 suppresses apoptosis through deacetylating and stabilizing the antiapoptotic protein Diap1.
  10. Evolution of host manipulation specificity in trophically transmitted parasites.
  11. Structural basis for the inhibition of Trypanosoma brucei enolase by a camelid single-domain antibody.
  12. Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8+ T-cell dysfunction in cancer.
  13. SLC25A51 and mitochondrial NAD⁺ transport in acute myeloid leukemia: mechanisms, therapeutic potential, and translational perspectives.
  14. Histone deacetylase inhibition ameliorates kidney injury by restoring fibroblast features to myofibroblasts.
  15. Positive feedback loop via HIF-1α lactylation driven by kynurenine promotes glycolysis.
  1. FASEB Bioadv. 2026 Jul;8(7): e70136
    Simulated Microgravity Reprograms Host Cell Architecture and Mitochondrial Function, Altering Toxoplasma gondii Growth.
    Musfika Tasnim Shirin, Takafumi Yamada, Daisuke Kondoh, Hiroki Bochimoto, Kentaro Kato.
      Simulated microgravity (SMG or μG) influences Toxoplasma gondii growth and modifies the cellular structure and function of the host cells. As an obligate intracellular parasite, Toxoplasma gondii depends on the metabolic activity and mitochondrial function of its host. However, the impact of SMG on host-pathogen interactions remains unclear. We investigated the effect of SMG on host cell structure and mitochondrial functions and its impact on Toxoplasma gondii infection. Cultured human foreskin fibroblasts (HFF) and Vero cells under SMG formed stratified cell layers and exhibited morphological mitochondrial abnormalities, such as outer membrane distortion and inner membrane distension. Functional analyses revealed altered mitochondrial membrane potential and intracellular ATP levels without substantial changes in reactive oxygen species. Upon infection, T. gondii showed cell-type-dependent growth, increasing in Vero cells but decreasing in HFF at 48 h post-infection. These findings indicate that SMG-induced mitochondrial remodeling is associated with altered host cell susceptibility to toxoplasmosis. Our study highlights the role of physical environmental changes in modulating host-pathogen interactions in the context of host cell mitochondrial function.
    Keywords:  ATP; HFF; ROS; Toxoplasma gondii; Vero cells; mitochondria; mitochondrial membrane potential; simulated microgravity
    DOI:  https://doi.org/10.1096/fba.2026-00146
  2. PLoS Pathog. 2026 Jul 24. 22(7): e1014451
    Phosphatidylinositol-4-phosphate signaling regulates dense granule biogenesis and maturation in Toxoplasma gondii.
    Angela Arabiotorre, Megan Formanowicz, Vytas A Bankaitis, Aby Grabon.
      Phosphoinositide metabolism defines the foundation of a major signaling pathway that is conserved throughout the eukaryotic kingdom. Although the 4-OH phosphorylated phosphoinositides phosphatidylinositol-4-phosphate (PtdIns4P) and phosphatidylinositol-4,5-bisphosphate are each individually required for the viability of all eukaryotic cells studied thus far, their activities in parasite biology are less well understood. Using intracellular tachyzoites of the apicomplexan parasite Toxoplasma gondii as model for studying PtdIns4P signaling in a protozoan, we demonstrate the presence of PtdIns4P pools in Golgi/trans-Golgi (TGN) system and in post-TGN compartments of the parasite. Moreover, using a combination of super-resolution confocal microscopy and correlative light electron microscopy, we show that deficits in PtdIns4P signaling result in structural perturbation of compartments that house dense granule cargo with accompanying deficits in dense granule exocytosis. Taken together, the data report a direct role for PtdIns4P in dense granule biogenesis and exocytosis. The data further suggest that the biogenic pathway for secretion-competent dense granule formation in T. gondii is more complex than simple budding of fully matured dense granules from the TGN.
    DOI:  https://doi.org/10.1371/journal.ppat.1014451
  3. PLoS One. 2026 ;21(7): e0354414
    Expression of Concern: Molecular prevalence, phylogeny and hematological impact of Toxoplasma gondii and Plasmodium spp. in common quails from Punjab, Pakistan.
    PLOS One Editors
      
    DOI:  https://doi.org/10.1371/journal.pone.0354414
  4. Acta Trop. 2026 Jul 23. pii: S0001-706X(26)00278-0. [Epub ahead of print] 108245
    Immunogenicity and Protective Efficacy of a Toxoplasma gondii Glycoprotein-Enriched Fraction in Mice.
    Eman E El Shanawany, Eman H Abdel-Rahman, Soad E Hassan, Hassan M Desouky, Amany Ebrahim Nofal, Raafat M Shaapan, Salwa Sami Younis.
      Toxoplasma gondii remains a significant parasitic pathogen with limited effective vaccines against its acute virulent form. This study aimed to evaluate the protective and immunological efficacy of a total glycoprotein-based vaccine isolated from T. gondii tachyzoites against infection with the virulent RH strain in Swiss albino mice. A glycoprotein-enriched fraction was isolated from T. gondii tachyzoites using Concanavalin A affinity column chromatography. Mice were divided into four groups (n=12/group): group I received three subcutaneous doses of 25 μg total isolated glycoproteins emulsified in Freund's adjuvant; goup II received adjuvant only; group III served as control positive (infected, non-vaccinated); Group IV served as control negative. Two weeks after the final dose, groups I-III were challenged intraperitoneally with 2,500 tachyzoites of the RH strain. Survival, parasite load, antibody responses, cytokine levels (IFN-γ, IL-12, IL-17), histopathological changes, and CD4+/CD8+ cell infiltration were evaluated. Vaccinated mice (group I) showed a 60% survival rate, with significantly prolonged survival (13.77 ± 0.878 days) compared to controls. Parasite load in peritoneal fluid and liver was reduced by 99.8% and 98.6%, respectively. Vaccination induced a significant increase in antigen-specific IgG and pro-inflammatory cytokines (IFN-γ, IL-12, and IL-17), suggesting a potent Th1/Th17-mediated immune response. Histopathological and immunohistochemical analyses confirmed reduced tissue damage, absence of tachyzoites, and enhanced CD4+/CD8+ T cell infiltration in the vaccinated group. In conclusion, the glycoprotein-based fraction provided significant protection against acute toxoplasmosis, demonstrating potential for further development as a subunit vaccine candidate.
    Keywords:  Acute toxoplasmosis; Cytokines; Glycoprotein vaccine; Immune response; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.actatropica.2026.108245
  5. Parasite Immunol. 2026 Jul;48(7): e70095
    An Immunoinformatic Approach for a Multi-Epitope Vaccine Against Toxoplasma gondii.
    Negar Asadi, Leila Navapour, Navid Mogharrab, Elham Yousefi, Sadegh Feizollahzadeh, Mortaza Taheri-Anganeh, Shahram Khademvatan, Gordon S Howarth.
      Infection with the intracellular apicomplexan parasite Toxoplasma gondii causes severe and often fatal clinical outcomes worldwide, especially in patients with immunodeficiency, diabetes and in pregnant women and infants. Despite approximately one-third of the global population being infected with T. gondii, there is currently no effective vaccine available for humans. The objective was to develop a potential vaccine candidate for T. gondii, which would incorporate the B- and T-lymphocyte epitopes derived from three immunogenic antigens of the parasite. Initially, the immunodominant epitopes present in the SAG1, GRA6 and GRA7 proteins of T. gondii were identified. Following this, a multi-epitope vaccine was developed by integrating B-cell epitopes, CTL epitopes and HTL epitopes, with the addition of the 50S ribosomal protein L7/L12 serving as an adjuvant to enhance the immunogenic properties of the vaccine. All identified epitopes demonstrated characteristics of being antigenic, nonallergenic, nontoxic and lacking human homologues. Furthermore, the candidate vaccine exhibited immunogenicity, non-allergenicity and stability. Molecular docking studies indicated robust interactions between the vaccine construct and the TLR-4 immune receptor. Additionally, the stability of the formulated vaccine was confirmed through molecular dynamic simulations. In silico analyses suggested that the vaccine construct could effectively initiate primary immune responses; however, further laboratory evaluations are required to verify its efficacy and safety.
    Keywords:   Toxoplasma gondii ; antigens; bioinformatics; multi‐epitope; vaccines
    DOI:  https://doi.org/10.1111/pim.70095
  6. Mol Microbiol. 2026 Jul 19.
    Divergent Autophagy Pathways in Plasmodium: Mechanisms, Functions, and Therapeutic Potential.
    Suryansh Rajput, Pragya Mehra, Rohini Nandi, Raksha Devi, Eisha Pandey, Aastha Varshney, Satish Mishra.
      Autophagy is a highly conserved degradative and recycling pathway essential for maintaining cellular homeostasis. Although its molecular machinery is well characterized in yeast and mammalian systems, it is less studied in the early-diverging apicomplexan parasite Plasmodium, the causative agent of malaria. Plasmodium possesses a reduced yet functional repertoire of autophagy-related (ATG) proteins, suggesting adaptations of this pathway to parasite-specific biology. Among these, ATG8, a ubiquitin-like protein, has emerged as a central marker and key effector of plasmodial autophagy. Its branched localization and association with the relict plastid (apicoplast) membrane indicate roles beyond canonical degradative autophagy, particularly in organelle maintenance and biogenesis. ATG7, an essential E1-like enzyme, activates ATG8 and facilitates its lipidation, thereby regulating organelle turnover and development. This process is further supported by a conserved conjugation system involving ATG3 (E2-like enzyme) and the ATG12, ATG5, ATG16 complex, functioning as a ligase to enable ATG8 membrane association. ATG4, a cysteine protease, is critical for recycling lipidated ATG8 and maintaining its cytosolic pool, while the homolog Otu can partially compensate for its function. ATG18 also plays an important role in apicoplast biogenesis and maintenance. Collectively, these findings highlight both canonical and non-canonical roles of autophagy proteins in Plasmodium, driving metabolic reprogramming, intracellular remodeling, and stage-specific differentiation, and support their potential as targets for new antimalarial therapies.
    Keywords:   Plasmodium ; ATG8; apicoplast; autophagy; drug resistance; non‐canonical autophagy
    DOI:  https://doi.org/10.1111/mmi.70096
  7. J Biol Chem. 2026 Jul 21. pii: S0021-9258(26)02218-0. [Epub ahead of print] 113346
    Cyclic GMP-dependent activation of Ca2+ release from the ER and digestive vacuole at distinct phases of intraerythrocytic Plasmodium falciparum development.
    Maneesh K Singh, Rute I Honorio, Paula J Bartlett, Celia R S Garcia, Andrew P Thomas.
      The malaria parasite Plasmodium falciparum relies on coordinated signaling cascades to control progression through its complex life cycle in the mammalian host and insect vector. Mobilization of cytosolic Ca2+ ([Ca2+]c) is central to many of these processes and is linked to the second messengers cyclic GMP (cGMP), cyclic AMP and inositol 1,4,5-trisphosphate (IP3). During the symptomatic blood stage these signaling pathways play key roles in erythrocyte invasion, maturation and egress of the parasite. Intraerythrocytic P. falciparum expressing the genetically encoded Ca2+ indicator GCaMP3 were used to investigate [Ca2+]c signals elicited by the cGMP phosphodiesterase inhibitor zaprinast during the late trophozoite and schizont stages, using post-hoc Hoechst staining to categorize the parasites. Zaprinast elicited two distinct phases of [Ca2+]c increase with the first appearing only in parasites in which DNA replication was already underway and the second arising later in schizogony. Both phases were dependent on activation of protein kinase G and could be mimicked by the cGMP analog 8-Br-cGMP. The first phase occurred as a transient [Ca2+]c increase derived from cyclopiazonic acid-sensitive endoplasmic reticulum Ca2+ stores and was suppressed by the IP3 signaling inhibitor 2-aminoethoxydiphenyl borate. The second phase [Ca2+]c increase induced by zaprinast was kinetically distinct and unaffected by cyclopiazonic acid, but was selectively eliminated by chloroquine, suggesting that it is derived from the digestive vacuole. These findings demonstrate that two separate Ca2+ mobilization pathways under the control of cGMP contribute to the [Ca2+]c signals that become active during schizogony in preparation for egress from the erythrocyte.
    Keywords:  Ca(2+) signaling; Malaria; cyclic GMP-dependent protein kinase; digestive vacuole; zaprinast
    DOI:  https://doi.org/10.1016/j.jbc.2026.113346
  8. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2608709123
    Antimalarial cytoskeletal targeting with broad apicomplexan activity.
    Darshan V Trivedi, Anastasia Karabina, Tiantian Jiang, Daisy Chen, Nimisha Mittal, Tonnie Huijs, Rianne van der Laak, Jin H Jeon, Tomas Yeo, Dihia Moussaoui, James P Robblee, Marianna Akey, Matthew Freese, Lorraine Fuller, Gustave Bergnes, Alice Racca, Heba Wander, Seongwon Jung, Stephanie Ouchida, Paul V Ruijgrok, Dan Song, Annamma Spudich, Kathleen M Ruppel, Suman Nag, Christoph Mueller-Dieckmann, Jeremy N Burrows, Benoît Laleu, Rafael Victorio Carvalho Guido, Anna Caroline Campos Aguiar, Dhelio Batista Pereira, Sergio Wittlin, Partha Mukherjee, Arnish Chakraborty, Samuel E Aggrey, Julien Robert-Paganin, Kathleen M Trybus, L David Sibley, Anne Houdusse, David A Fidock, Koen J Dechering, Elizabeth A Winzeler, James A Spudich.
      Malaria is a devastating disease that resulted in an estimated 610,000 deaths in 2024, the majority being children under the age of five. Here, we use KNX-115 to illustrate multistage antiparasitic activity upon targeting the cytoskeletal enzyme Plasmodium falciparum myosin A (PfMyoA). KNX-115 inhibits purified actin-activated ATPase with a potency in the low nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 traps PfMyoA in a state that binds weakly to actin. A 2.35 Å resolution structure of KNX-115 bound to PfMyoA reveals critical interactions contributing to its mechanism of action. Importantly, in vitro evolution data reveal that KNX-115 engages PfMyoA as a sole cellular target. Inhibiting PfMyoA blocks the development of the blood and liver stages of laboratory strains of P. falciparum, with no liver cell toxicity, sporozoite cell traversal and motility, and sporozoite development in the mosquito. Inhibiting PfMyoA completely kills parasites after 96 h of treatment. Furthermore, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials and shows inhibitory activity against P. falciparum circulating isolates from the Brazilian Amazon. Inhibiting PfMyoA with KNX-115 also blocks the blood stage of a laboratory strain of Plasmodium vivax. In line with the evolutionary identity of MyoA among various apicomplexan parasites, KNX-115 also inhibits Cryptosporidium and Eimeria MyoA in vitro and is an effective inhibitor of Cryptosporidium, Toxoplasma, and Eimeria cellular growth, with EC50s similar to those found for blood and liver stage Plasmodium.
    Keywords:  MyoA inhibitor; malaria; myosin; parasitic diseases
    DOI:  https://doi.org/10.1073/pnas.2608709123
  9. Sci Adv. 2026 Jul 24. 12(30): eaeg2060
    Hdac3 suppresses apoptosis through deacetylating and stabilizing the antiapoptotic protein Diap1.
    Dafa Zhou, Bin Liu, Yan Ding, Yujiao Wang, Yuanfei Sun, Simin Xu, Hui Li, Xiaopei Wang, Yunhe Zhao, Qingxin Liu, Zizhang Zhou.
      Apoptosis is a highly conserved process that eliminates unwanted or damaged cells in both physiological and pathological conditions. Dysregulation of apoptosis leads to developmental abnormalities and various diseases, such as neurodegeneration and cancer. Drosophila inhibitor of apoptosis 1 (Diap1) plays a crucial role in cell survival by inhibiting caspases and preventing apoptosis. However, under stress conditions, the prodeath proteins Rpr, Hid, and Grim (RHG) induce apoptosis by antagonizing Diap1. Despite being a key component of the apoptotic pathway, the mechanism that controls the stability of Diap1 remains unknown. Here, we find that loss of hdac3 results in the activation of apoptosis, which is completely blocked by expressing Diap1. Although Hdac3 localizes in both the cell cytoplasm and nucleus, only the cytoplasmic Hdac3 is able to suppress apoptosis induced by hdac3 deficiency, RHG overexpression, or x-ray irradiation. This finding indicates that Hdac3 exerts an antiapoptotic role independent of its canonical epigenetic functions. Loss of hdac3 decreases Diap1 protein, which is rescued by introducing cytoplasmic Hdac3. The deacetylase activity is necessary for Hdac3 to suppress apoptosis. Mechanistically, Hdac3 interacts with Diap1 to remove the acetyl group from K315 on Diap1, thereby increasing its stability. Compared with the wild-type Diap1, the acetyl-deficient mutant Diap1-K315R exhibits stronger stability and antiapoptotic activity. Last, RHG proteins compete with Hdac3 for Diap1 interaction, directing Diap1 toward degradation and triggering apoptosis. Together, these findings not only reveal the involvement of Diap1 acetylation modification in apoptosis regulation but also clarify the role of Hdac3 in apoptosis.
    DOI:  https://doi.org/10.1126/sciadv.aeg2060
  10. J Evol Biol. 2026 Jul 23. pii: voag064. [Epub ahead of print]
    Evolution of host manipulation specificity in trophically transmitted parasites.
    Otto Seppälä.
      Trophically transmitted parasites frequently alter the phenotype of their intermediate host to increase predation by the next host in the life cycle. Still, the degree to which such manipulation is specific to the correct predator varies widely across systems. Some parasites employ mechanisms that selectively increase vulnerability to the next host, whereas others increase predation indiscriminately, exposing the parasite to dead-end predators. Despite growing empirical documentation of this variation, no theoretical model has addressed the evolution of manipulation specificity itself. Here, I develop a general analytical model in which a trophically transmitted parasite evolves two traits simultaneously: manipulation intensity and manipulation leakage-the degree to which parasite-induced changes in host vulnerability extend to non-host predators. The parasite faces three competing outcomes in its intermediate host: predation by the suitable next host (transmission), predation by non-host predators (dead end), and natural non-predation mortality. I derive the condition for manipulation to be favoured, obtain the joint evolutionarily stable strategy for intensity and leakage, and provide an analytical approximation for the equilibrium. The model reveals that although dead-end predation creates the selective incentive for specificity, specificity evolves only when the fecundity costs of achieving it are sufficiently low. This condition is determined by the manipulation pathway, not by the intensity of non-host predation.
    Keywords:  complex life cycle; dead-end predator; evolutionarily stable strategy; host manipulation; leakage; parasite transmission; predation; trophic transmission
    DOI:  https://doi.org/10.1093/jeb/voag064
  11. Mol Biochem Parasitol. 2026 Jul 22. pii: S0166-6851(26)00042-3. [Epub ahead of print] 111763
    Structural basis for the inhibition of Trypanosoma brucei enolase by a camelid single-domain antibody.
    Zeng Li, Natalia Smiejkowska, Julie Vansevenant, Jimmy Mertens, Pieter Van Wielendaele, Joar Esteban Pinto Torres, Stefan Magez, Yann G-J Sterckx.
      Trypanosoma brucei is an extracellular protozoan that causes neglected tropical diseases in both humans and livestock. The parasite has a bipartite life cycle involving an insect vector and a mammalian host. Within the latter, it mainly thrives as a blood-borne parasite that relies on glycolysis to support its energy metabolism. It is for this reason that trypanosomal glycolytic enzymes have been investigated as potential targets for the development of trypanosome-killing drugs. Recent work from our lab has shown that they are also interesting biomarkers for the detection of active trypanosome infections. T. brucei enolase (TbrENO) is a trypanosomal glycolytic enzyme that has gathered interest in both drug and diagnostics development. In this paper, we report the discovery of a camelid single domain antibody (sdAb aka nanobody) that specifically recognises and inhibits TbrENO. The sdAb's inhibitory mechanism is unraveled through a combination of protein biochemistry, biophysics, and structural biology.
    DOI:  https://doi.org/10.1016/j.molbiopara.2026.111763
  12. Immunometabolism (Cobham). 2026 Jul;8(3): e00086
    Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8+ T-cell dysfunction in cancer.
    Desh Raj, Mahesh Kathania, Tuoqi Wu, Arianne L Theiss, K Venuprasad.
      In a recent study published in Science Immunology, Tiberti and colleagues demonstrate that palmitate, a saturated fatty acid enriched in tumors, directly impairs CD8+ cytotoxic T lymphocyte function through mitochondrial and epigenetic reprogramming. Palmitate exposure reduced mitochondrial fitness, oxidative phosphorylation, and adenosine triphosphate production, resulting in defective proliferation, cytokine production, and antitumor activity. Mechanistically, mitochondrial dysfunction decreased intracellular acetyl-CoA availability, leading to reduced histone acetylation and loss of chromatin accessibility at loci that control effector programs. The study further identifies sphingosine kinase 2 as a critical mediator of lipid-induced dysfunction. Importantly, SPHK2 inhibition restored mitochondrial function, histone acetylation, and cytotoxic T lymphocyte antitumor activity, highlighting a potential therapeutic strategy for enhancing cancer immunotherapy.
    Keywords:  T-cell exhaustion; acetyl CoA; cytotoxic T cells; palmitate
    DOI:  https://doi.org/10.1097/IN9.0000000000000086
  13. Hum Cell. 2026 Jul 19. pii: 111. [Epub ahead of print]39(8):
    SLC25A51 and mitochondrial NAD⁺ transport in acute myeloid leukemia: mechanisms, therapeutic potential, and translational perspectives.
    Chunmeng Rong, Ruixiu Chen, Hanqi Lou, Yongming Xia, Shiwei Duan.
      Acute myeloid leukemia (AML) remains a highly lethal hematologic malignancy characterized by metabolic reprogramming, therapeutic resistance, and poor survival, particularly in older patients. Nicotinamide adenine dinucleotide (NAD⁺) metabolism has emerged as a central driver of AML progression, and recent studies have identified solute carrier family 25 member 51 (SLC25A51) as the primary mitochondrial NAD⁺ transporter in mammalian cells. SLC25A51 regulates mitochondrial redox balance, oxidative phosphorylation, and tricarboxylic acid (TCA) cycle activity, thereby sustaining leukemic proliferation and survival. Structural studies have elucidated its six-transmembrane helix architecture, salt-bridge-mediated transport mechanism, and stabilization by cardiolipin binding. Functional investigations demonstrate that SLC25A51 overexpression correlates with poor prognosis, while its depletion disrupts mitochondrial metabolism, induces apoptosis, and suppresses AML progression in vivo. Therapeutically, pharmacologic inhibition of SLC25A51 with fludarabine, or its combination with hypomethylating agents, such as 5-azacytidine, enhances antileukemic efficacy by perturbing metabolic and epigenetic regulation. Moreover, SLC25A51 expression may serve as a predictive biomarker for mitochondrial-targeted therapies, such as complex I inhibitors. Future translational research should focus on developing selective inhibitors, optimizing combination strategies with demethylating agents and BCL-2 inhibitors, and validating its prognostic significance in clinical cohorts. Collectively, SLC25A51 represents a promising metabolic target with potential to overcome therapeutic resistance and improve patient outcomes in AML. Furthermore, this review discusses its potential implications across distinct genetic subtypes of AML (e.g., mutations in TP53, NPM1, and RAS), thereby highlighting key directions for future translational research.
    Keywords:  Acute myeloid leukemia (AML); Metabolic reprogramming; Mitochondrial NAD⁺ transport; SLC25A51; Targeted therapy
    DOI:  https://doi.org/10.1007/s13577-026-01428-7
  14. Life Sci. 2026 Jul 20. pii: S0024-3205(26)00408-X. [Epub ahead of print]402 124599
    Histone deacetylase inhibition ameliorates kidney injury by restoring fibroblast features to myofibroblasts.
    Hirotaka Ishioka, Yuma Iwamura, Yusuke Konta, Koji Sato, Koichiro Kato, Tetsuhiro Tanaka, Taku Nakai, Norio Suzuki.
       AIMS: There are no effective strategies for treating chronic kidney disease (CKD) because of the limited understanding of its complex pathology. Fibrosis commonly develops and expands during CKD progression, making it a plausible therapeutic target against CKD. We have previously reported that kidney disease induces the myofibroblastic transformation of renal interstitial fibroblasts, which produce the erythroid growth factor erythropoietin, thereby promoting fibrosis through the production of extracellular matrix and leading to erythropoietin-deficiency anaemia. Since histone deacetylases (HDACs) govern cellular differentiation status, this study investigated whether HDAC inhibition could ameliorate renal fibrosis through restoring myofibroblasts to fibroblastic cells.
    METHODS: Changes in the gene expression profile and morphology of a myofibroblast line derived from murine renal fibroblasts were assessed after incubation with HDAC inhibitors or inactivation of HDAC isoform expression. The effects of pharmacological HDAC inhibition were also evaluated using CKD model mice and primary-cultured renal myofibroblasts obtained from the urine of a patient with CKD.
    KEY FINDINGS: HDAC inhibitors shifted the gene expression signature of myofibroblasts towards that of fibroblasts and induced morphological changes. HDAC2 knockdown partially recapitulated these effects, whereas HDAC1 knockdown failed because of cell death. HDAC inhibition significantly attenuated genes related to fibrosis and tubular damage, with similar trends histologically observed. In patient-derived renal myofibroblasts, HDAC inhibition suppressed profibrotic gene expression and restored erythropoietin gene expression.
    SIGNIFICANCE: HDAC inhibition suppresses renal fibrosis through the induction of apoptosis and restores fibroblast features in myofibroblasts, potentially leading to the amelioration of tubular damage and erythropoietin insufficiency in patients with CKD.
    Keywords:  Chronic kidney disease; Erythropoietin; Histone deacetylase inhibitors; Renal fibrosis
    DOI:  https://doi.org/10.1016/j.lfs.2026.124599
  15. Oncogene. 2026 Jul 23.
    Positive feedback loop via HIF-1α lactylation driven by kynurenine promotes glycolysis.
    Shuoqi Lin, Yuxiang Yan, Junlin Zhou, Genggeng Zheng, Tesen Liao, Youguang Lu, Bohua Su, Dali Zheng.
      Tryptophan metabolism undergoes marked alterations in OSCC, leading to an abnormal accumulation of the metabolite kynurenine. Nonetheless, how kynurenine, a key intermediate of tryptophan metabolism, contributes to tumor metabolic reprogramming is still not well clarified. Here, we identify Kyn as a metabolic signal that drives glycolytic reprogramming and promotes tumor progression. Mechanistically, Kyn functionally associates with AKT and enhances AKT-dependent mTOR phosphorylation, leading to subsequent activation of the mTOR which facilitates the dissociation of eIF4EBP1 from eIF4E, thereby enhancing cap-dependent translation of HIF-1α. Elevated HIF-1α upregulates glycolytic enzymes, accelerating glycolytic flux and increasing lactate production. The accumulated lactate in turn stabilizes HIF-1α through lysine lactylation, thereby establishing a reinforcing feedback cycle that enhances glycolytic activity and supports continuous tumor expansion. Collectively, our results uncover an unappreciated metabolic regulatory loop in which kynurenine promotes glycolysis via AKT/mTOR-mediated translational activation and HIF-1α lactylation, highlighting a mechanistic link between tryptophan metabolism and glucose metabolism. These insights provide a rationale for combined therapeutic strategies targeting the kynurenine pathway and glycolysis in OSCC.
    DOI:  https://doi.org/10.1038/s41388-026-03916-4
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