bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2025–08–31
23 papers selected by
Lakesh Kumar, BITS Pilani
  1. Toxoplasma gondii PPM3H regulates the parasite virulence and modulates host immune and inflammatory responses in mice.
  2. A Major Facilitator Superfamily Transporter Is Critical for the Metabolism and Biogenesis of the Apicoplast.
  3. Research on inner membrane complex protein 1: a novel nanovaccines against Toxoplasma gondii.
  4. Class I histone deacetylases catalyze lysine lactylation.
  5. Protective Efficacy Induced by Virus-like Particles Expressing Dense Granule Protein 5 of Toxoplasma gondii.
  6. Immunogenicity and Protective Efficacy of a Recombinant Toxoplasma gondii GRA12 Vaccine in Domestic Cats.
  7. Toxoplasma gondii at the Host Interface: Immune Modulation and Translational Strategies for Infection Control.
  8. Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites.
  9. Insights Into the Role of Lysine Acetylation of Non-Histone Proteins in Plant Immunity.
  10. Review of Toxoplasmosis: What We Still Need to Do.
  11. Dynamic Regulation of RNA m6A Methylation in the Ribonucleoprotein Complexes in Apicomplexan and Kinetoplastid Parasites.
  12. Class IIa HDACs Are Important Signal Transducers with Unclear Enzymatic Activities.
  13. Regulators of Cancer Progression: Succinylation.
  14. Sirtuins as mediators and targets of arsenic toxicity: unraveling signaling pathway crosstalk.
  15. Targeted CRISPR screens reveal genes essential for Cryptosporidium survival in the host intestine.
  16. In Vivo Safety and Efficacy of Thiosemicarbazones in Experimental Mice Infected with Toxoplasma gondii Oocysts.
  17. Gene expression profiling in cardiac tissue of mice chronically infected with Toxoplasma gondii: implications for immune response pathways.
  18. Roles of SIRT3 in aging and aging-related diseases.
  19. Deacetylation of ATG16L1 is required for LC3-associated lysosomal microautophagy.
  20. Crosstalk Between Lysine Lactylation and Acetylation Regulates Lactate Dehydrogenase in Streptococcus mutans.
  21. Eimeria tenella AMA1 regulates host cell apoptosis through the mitochondrial pathway and the death receptor pathway.
  22. An efficient machine-learning framework for predicting protein post-translational modification sites.
  23. The role of phosphatidylcholine metabolism in tumors.
  1. Vet Res. 2025 Aug 26. 56(1): 171
    Toxoplasma gondii PPM3H regulates the parasite virulence and modulates host immune and inflammatory responses in mice.
    Jun-Jun He, Jun Ma, Meng-Ling Deng, Hany M Elsheikha, Yi-Dan Wang, Yu-Cong Zhang, Feng-Cai Zou, Xing-Quan Zhu.
      Toxoplasma gondii is an obligate intracellular parasite that causes severe illness in infants infected during pregnancy and in immunocompromised individuals. This parasite manipulates host cells through effector proteins that promote its survival and replication. While the phosphatases in the PP2C family have been shown to regulate host immune responses and contribute to the virulence and pathogenicity of various pathogens, the specific biological functions of PPM3H in T. gondii and its role in host-pathogen interactions remain unclear. In this study, we demonstrate that knockout of ppm3h significantly reduces the virulence and pathogenicity of T. gondii. In contrast, that high expression of ppm3h in the less virulent PRU induced by replacing the ppm3h gene elements of RH strain can enhance its pathogenicity, indicating a direct contribution of PPM3H to virulence in expression-independent manner. Furthermore, PPM3H significantly influenced host gene expression, with differentially expressed genes predominantly enriched in immune and inflammatory pathways. Weighted gene co-expression network analysis identified host immune genes, including chemokines such as Cx3cl1 and Ccl22, as co-expressed with ppm3h. Also, ppm3h co-expressed with T. gondii rhoptry genes including rop18, a well-known virulence factor, suggesting a role for PPM3H in coordinating host-pathogen interactions. Our findings establish that PPM3H enhances T. gondii virulence by modulating the host immune and inflammatory responses. PPM3H does not impact parasite gene expression, invasion or replication in vitro, supporting its role as an immune modulator rather than a general fitness factor. This suggests that T. gondii's pathogenicity arises not only from immune evasion but also from the active induction of host immune and inflammatory responses mediated by PPM3H.
    Keywords:   Toxoplasma gondii ; PP2C phosphatases; PPM3H; host–pathogen interaction; parasite effector proteins; virulence
    DOI:  https://doi.org/10.1186/s13567-025-01603-y
  2. Pathogens. 2025 Aug 01. pii: 763. [Epub ahead of print]14(8):
    A Major Facilitator Superfamily Transporter Is Critical for the Metabolism and Biogenesis of the Apicoplast.
    Yumeng Liang, Wei Qi, Jiawen Fu, Honglin Jia.
      The apicoplast is a highly specialized organelle in the biosynthesis of essential metabolites in most of the apicomplexan protozoa. This organelle is surrounded by four layers of membranes. However, the molecular mechanisms mediating transmembrane transport are not yet fully understood. In this study, we conducted a phenotypic analysis to investigate the role of a major facilitator superfamily transporter (TgApMFS1) in the survival of the parasite. The results indicated that TgApMFS1 is critical for the survival of Toxoplasma gondii in cell culture conditions. Further analysis indicated that these transporters are crucial for the biogenesis of organelles and the metabolic processes of parasite.
    Keywords:  MFS transporter; Toxoplasma gondii; apicoplast; biogenesis; metabolic activity
    DOI:  https://doi.org/10.3390/pathogens14080763
  3. BMC Vet Res. 2025 Aug 23. 21(1): 521
    Research on inner membrane complex protein 1: a novel nanovaccines against Toxoplasma gondii.
    YunNan Fang, Pan Zhou, WeiYu Qi, YanLi Yu, XiaoJuan Wang, YuChen Jiang, Li Zhang, YouLi Yu, JianDong Wang, ZhengQing Yu, TingLi Liu.
      Toxoplasma gondii (T. gondii) is a globally prevalent zoonotic parasite causing severe health and economic impacts. Despite decades of research, no commercial vaccine provides comprehensive protection against both acute and chronic toxoplasmosis. DNA vaccines represent a promising strategy, but their application is hindered by low delivery efficiency and limited immunogenicity. Here, we developed and evaluated pVAX1-TgIMC1-loaded PLGA and chitosan (CS) nanospheres as potential vaccine candidates. Immunization studies in mice showed that pVAX1-TgIMC1/PLGA and pVAX1-TgIMC1/CS nanospheres induced robust humoral and cellular immune responses, significantly enhancing specific IgG levels and cytokine production IFN-γ and IL-17 compared to the naked DNA vaccine. Both nanospheres also promoted dendritic cell maturation and T-cell activation, resulting in reduced parasite burdens in cardiac tissues post-challenge. Notably, the PLGA nanospheres exhibited superior protection against acute toxoplasmosis, while CS nanospheres provided additional advantages in antigen stability and delivery. The nanospheres were non-toxic, as confirmed by biochemical markers and histopathological analysis. These findings highlight pVAX1-TgIMC1/PLGA and pVAX1-TgIMC1/CS nanospheres as promising candidates for T. gondii vaccine development, warranting further optimization and validation in broader animal models.
    Keywords:   Toxoplasma gondii ; Immunoprotection; Inner membrane complex 1; Nanomaterial nanospheres
    DOI:  https://doi.org/10.1186/s12917-025-04961-z
  4. J Biol Chem. 2025 Aug 18. pii: S0021-9258(25)02453-6. [Epub ahead of print] 110602
    Class I histone deacetylases catalyze lysine lactylation.
    Michelangelo B Gonzatti, Jordi C J Hintzen, Isha Sharma, Mohd Altaf Najar, Takeshi Tsusaka, Mariola M Marcinkiewicz, Claudia Veronica Da Silva Crispim, Nathaniel W Snyder, George M Burslem, Emily L Goldberg.
      Metabolism and post-translational modifications (PTMs) are intrinsically linked and the number of identified metabolites that can covalently modify proteins continues to increase. This metabolism/PTM crosstalk is especially true for lactate, the product of anaerobic metabolism following glycolysis. Lactate forms an amide bond with the ε-amino group of lysine, a modification known as lysine lactylation, or Kla. Multiple independent mechanisms have been proposed in the formation of Kla, including p300/CBP-dependent transfer from lactyl-CoA, a reactive intermediate lactoylglutathione species that non-enzymatically lactylates proteins, and several enzymes are reported to have lactyl transferase capability. We recently discovered that class I histone deacetylases (HDACs) 1, 2, and 3 can all reverse their canonical chemical reaction to catalyze lysine β-hydroxybutyrylation. Here we tested the hypothesis that HDACs can also catalyze Kla formation. Using biochemical, pharmacological, and genetic approaches, we found that HDACs are sufficient to catalyze Kla formation and that HDACs are a major driver of lysine lactylation. Dialysis experiments confirm this is a reversible reaction that depends on lactate concentration. We also directly quantified intracellular lactyl-CoA and found that Kla abundance can be uncoupled from lactyl-CoA levels. Therefore, we propose a model in which the majority of Kla is formed through enzymatic addition of lactate by HDACs 1, 2, and 3.
    Keywords:  glycolysis; histone deacetylase (HDAC); lactate; lactic acid; lysine lactylation; macrophage; post-translational modification (PTM); protein acylation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110602
  5. Vaccines (Basel). 2025 Jul 24. pii: 787. [Epub ahead of print]13(8):
    Protective Efficacy Induced by Virus-like Particles Expressing Dense Granule Protein 5 of Toxoplasma gondii.
    Su In Heo, Hae-Ji Kang, Jie Mao, Zhao-Shou Yang, Md Atique Ahmed, Fu-Shi Quan.
      Background:Toxoplasma gondii (T. gondii) causes severe disease in immunocompromised individuals and pregnant women, underscoring the urgent need for effective vaccines against toxoplasmosis. The dense granule protein 5 (GRA5) of T. gondii plays a key role in parasitic cyst formation. Methods: This study evaluated the protective immune responses induced by a virus-like particle (VLP) vaccine expressing the T. gondii-derived antigen GRA5 in a mouse model challenged with the ME49 strain of T. gondii. GRA5 VLPs were generated using a baculovirus expression system, and VLP formation was confirmed by Western blotting and visualized using transmission electron microscopy. Mice were intranasally immunized with GRA5 VLPs three times at 4-week intervals to induce immune responses, followed by infection with T. gondii ME49. Results: Intranasal immunization with GRA5 VLPs induced parasite-specific IgG antibody responses in the serum and both IgG and IgA antibody responses in the brain. Compared to the non-immunized group, immunized mice exhibited significantly higher levels of germinal center B cells and antibody-secreting cell responses. Moreover, the VLP vaccine suppressed the production of IFN-γ and IL-6 cytokines, leading to a significant reduction in brain inflammation and decreased cyst counts following lethal challenge with T. gondii ME49 infection. Conclusion: These findings suggest that the GRA5 VLP vaccine derived from T. gondii elicits a protective immune response, highlighting its potential as an effective vaccine candidate against toxoplasmosis.
    Keywords:  GRA5; Toxoplasma gondii; vaccine; virus-like particles
    DOI:  https://doi.org/10.3390/vaccines13080787
  6. Vaccines (Basel). 2025 Aug 11. pii: 851. [Epub ahead of print]13(8):
    Immunogenicity and Protective Efficacy of a Recombinant Toxoplasma gondii GRA12 Vaccine in Domestic Cats.
    Jinru Yang, Linchong Nie, Yining Song, Zipeng Yang, Liulu Yang, Hongjie Ren, Wenhao Li, Yasser Mahmmod, Xiu-Xiang Zhang, Ziguo Yuan, Hao Yuan, Yan Zhang.
      Background:Toxoplasma gondii (T. gondii) is a significant opportunistic zoonotic protozoan, presenting a substantial risk to human health and livestock. Consequently, the development of an effective vaccine against toxoplasmosis is imperative. This study focuses on the GRA12 protein as a target for developing a recombinant protein vaccine, with its efficacy evaluated through immunization trials in cats. Methods: We expressed recombinant GRA12 protein in E. coli and immunized cats with the purified antigen. The cats were categorized into four groups: G1 (PBS control), G2 (ISA 201 adjuvant alone), G3 (rGRA12 vaccine), and G4 (rGRA12 combined with ISA 201 adjuvant). All cats underwent subcutaneous immunizations on days 0, 14, and 28. Subsequently, serum levels of IgG (including IgG1 and IgG2a subclasses) and cytokines (IFN-γ, IL-2, TNF-α, IL-4, IL-10) were measured by enzyme-linked immunosorbent assay (ELISA). Two weeks after the third immunization (42 DPI), each cat was intraperitoneally infected with 1 × 106T. gondii RH tachyzoites. Oocyst shedding, survival duration, and T. gondii burden were monitored to assess vaccine-induced immunity. Results: The results indicate that immunization with recombinant rGRA12 protein significantly elevated IgG, IgG1, and IgG2a antibody levels in cats. G4 displayed elevated IgG levels post-immunization compared to G1 and G2, with an IgG1/IgG2a ratio > 1, indicating a mixed Th1/Th2 immune response. G4 also showed significantly increased IFN-γ, IL-2, TNF-α, and IL-4 levels compared to G1 (p < 0.05), while IL-10 remained unchanged. After T. gondii infection, total oocyst counts were 4.61 × 106 (G1), 4.49 × 106 (G2), 3.58 × 106 (G3), and 2.59 × 106 (G4), with G3/G4 showing 20.1-27.9% reduction relative to G1 (p < 0.05). Survival analysis revealed that groups G3 and G4 exhibited significantly longer median survival times (38 and 60 days, respectively; G4 with no mortality) compared to G1 and G2 (19 and 26 days, respectively). Additionally, parasite burdens in the brain, heart, lungs, liver, and spleen were significantly reduced in G3/G4 compared to G1/G2 (p < 0.01). Conclusions: In summary, the recombinant GRA12 vaccine significantly enhanced host survival and reduced parasite burden, demonstrating its potential as an effective toxoplasmosis vaccine candidate. These findings provide valuable data for future toxoplasmosis vaccine development.
    Keywords:  Toxoplasma gondii; cat; immune protection effect; rGRA12
    DOI:  https://doi.org/10.3390/vaccines13080851
  7. Vaccines (Basel). 2025 Jul 31. pii: 819. [Epub ahead of print]13(8):
    Toxoplasma gondii at the Host Interface: Immune Modulation and Translational Strategies for Infection Control.
    Billy J Erazo Flores, Laura J Knoll.
      Toxoplasma gondii is an intracellular protozoan found worldwide that is capable of infecting nearly all warm-blooded animals, including humans. Its parasitic success lies in its capacity to create chronic infections while avoiding immune detection, altering host immune responses, and disrupting programmed cell death pathways. This review examines the complex relationship between T. gondii and host immunity, focusing on how the parasite influences innate and adaptive immune responses to survive in immune-privileged tissues. We present recent findings on the immune modulation specific to various parasite strains, the immunopathology caused by imbalanced inflammation, and how the parasite undermines host cell death mechanisms such as apoptosis, necroptosis, and pyroptosis. These immune evasion tactics enable prolonged intracellular survival and pose significant challenges for treatment and vaccine development. We also review advancements in therapeutic strategies, including host-directed approaches, nanoparticle drug delivery, and CRISPR-based technologies, along with progress in vaccine development from subunit and DNA vaccines to live-attenuated candidates. This review emphasizes the importance of T. gondii as a model for chronic infections and points out potential avenues for developing innovative therapies and vaccines aimed at toxoplasmosis and similar intracellular pathogens.
    Keywords:  Toxoplasma gondii; host response; immune modulation; programmed cell death; therapies; vaccines
    DOI:  https://doi.org/10.3390/vaccines13080819
  8. Int J Parasitol Drugs Drug Resist. 2025 Aug 05. pii: S2211-3207(25)00029-6. [Epub ahead of print]29 100606
    Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites.
    Maria R Gancheva, Emma Y Mao, Ornella Romeo, Daniel Vuong, Ryan O'Handley, Stephen W Page, Ernest Lacey, Danny W Wilson.
      Frontline drug treatments for malaria are at risk of failing due to emerging resistance, meanwhile drugs used to treat toxoplasmosis have suboptimal efficacy and safety. As demonstrated by the success of clinically used antiparasitic drugs, the diverse structural complexity and biological activity of natural products holds great potential for drug discovery and development, to address the need for new compounds with novel mechanisms. Here we screened the BioAustralis Discovery Plates Series I library, a collection of 812 microbial natural product compounds including rare microbial metabolites, against Plasmodium falciparum erythrocytic stage and Toxoplasma gondii tachyzoite parasites. We identified 219 compounds that inhibited P. falciparum growth by at least 80 % at a concentration of 2 μg/mL (1-10 μM for >90 % of compounds), whilst 149 compounds demonstrated equivalent activity against T. gondii. The active compounds were assigned based on chemical structure to more than 50 compound classes. After triaging active compounds for those with low mammalian cytotoxicity, we defined the in vitro half maximal inhibitory concentration (IC50) of a selection of compounds against the parasites, identifying four compound groups with activity in the low nanomolar range. The macrocyclic lactone pladienolide B and cryptopleurine were found to be very potent against the parasites but also mammalian cells, warranting further structure-activity relationship investigation. Two groups, the monocyclic thiazole peptides, including micrococcin P1 and the thiocillins, and the pleuromutilins, exhibited both low antiparasitic IC50 and low cytotoxicity, highlighting their potential for further analysis. This study defines the activity of the BioAustralis Discovery Plates Series I against two apicomplexan parasites of significant global importance, providing potential new tools to study parasite biology and possible starting points for novel antiparasitic development.
    Keywords:  Drug discovery; Malaria; Natural products; Toxoplasmosis
    DOI:  https://doi.org/10.1016/j.ijpddr.2025.100606
  9. Plant Cell Environ. 2025 Aug 21.
    Insights Into the Role of Lysine Acetylation of Non-Histone Proteins in Plant Immunity.
    Jérémy Villette, Chloé Ilbert, Sébastien Aimé, Hoai-Nam Truong, Marielle Adrian, Stéphane Bourque.
      Plant immunity is regulated by numerous transcriptional and posttranslational mechanisms. Among these, lysine acetylation, which is controlled by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), has been extensively studied, particularly in the context of epigenetic regulation through histone acetylation. However, advances in proteomics have revealed that non-histone proteins also undergo lysine acetylation, prompting increasing efforts to elucidate the underlying mechanisms and functions of this posttranslational modifications. This review provides a comprehensive analysis of acetyl-lysine proteome (acetylome) studies during plant interaction with pathogens (including fungi, bacteria and viruses). By highlighting the significance of lysine acetylation in non-histone proteins, these studies offer valuable insights into potential new targets for lysine acetylation in plant immunity. We further examine the roles of plant KATs and KDACs, as well as pathogen-derived KATs, emphasizing the different types of lysine acetylation in non-histone proteins. In particular, we explore how bacterial effectors, which mimic KAT activity, acetylate lysine residues in non-histone proteins to modulate plant immunity. Additionally, we discuss on emerging molecular mechanisms involving plant KATs and KDACs that finely regulate immune responses, particularly within the jasmonic acid signalling pathway. These findings open new perspectives for future research on this posttranslational regulation within the context of plant immunity.
    Keywords:  effectors; lysine acetylation; non‐histone proteins; plant immunity
    DOI:  https://doi.org/10.1111/pce.70139
  10. Vet Sci. 2025 Aug 18. pii: 772. [Epub ahead of print]12(8):
    Review of Toxoplasmosis: What We Still Need to Do.
    Muhammad Farhab, Muhammad Waqar Aziz, Aftab Shaukat, Ming-Xing Cao, Zhaofeng Hou, Si-Yang Huang, Ling Li, Yu-Guo Yuan.
      Toxoplasma gondii is responsible for the disease toxoplasmosis and has the broadest host range among apicomplexan parasites, as it infects virtually all warm-blooded vertebrates. Toxoplasmosis is a zoonotic and emerging public health concern with considerable morbidity and mortality, especially in the developing world, affecting approximately one-third of the world's human population. Clinical presentation varies among species, and the infection establishes lifelong chronicity in hosts. Most of the host species (including healthy humans) are asymptomatic on the one hand, it is fatal to marsupials, neotropical primates and some marine mammals on the other hand. In immunocompetent humans, infection is typically asymptomatic, whereas immunocompromised individuals may develop disseminated disease affecting virtually any organ system-most commonly reproductive, cerebral, and ocular systems. Toxoplasmosis spreads by ingestion of food or water contaminated with T. gondii oocysts, consumption of undercooked/raw meat containing tissue cysts, transplacental transmission from mother to fetus, or by receiving infected organ/blood from the infected individual. Toxoplasmosis is mainly diagnosed by serologic tests and polymerase chain reaction (PCR). It is treated with pyrimethamine combined with sulfadiazine or clindamycin, often supplemented with leucovorin, atovaquone, and dexamethasone. Despite having many potent anti-T. gondii antigenic candidates, there is no commercially available vaccine for humans due to many factors, including the complex life cycle of the parasite and its evasion strategies. To date, the only commercially available anti-T. gondii vaccine is for sheep, licensed for veterinary use to prevent ovine abortions. In this review, we have summarized the current understanding of toxoplasmosis.
    Keywords:  Toxoplasma gondii; control; diagnosis; lifecycle; treatment
    DOI:  https://doi.org/10.3390/vetsci12080772
  11. Biomed J. 2025 Aug 20. pii: S2319-4170(25)00077-0. [Epub ahead of print] 100903
    Dynamic Regulation of RNA m6A Methylation in the Ribonucleoprotein Complexes in Apicomplexan and Kinetoplastid Parasites.
    Kaitlin Klotz, Carli Camporeale, Kausik Chakrabarti.
      m6A, or N6-methyladenosine, is a the most abundant modification of mRNA transcripts. These modifications are known to influence mRNA transcript stability, transcription, translation, alternative splicing and decay, with undoubtedly more functions to be discovered. In this review, we explored the roles of m6A modifications in two groups of protozoan parasites: the apicomplexans, which include Plasmodium and Toxoplasma species, and kinetoplastids, which include Trypanosoma and Leishmania species. We also compared the key players of m6A epitranscriptomic machinery in creating, interpreting, and removing m6A modifications between these parasitic protists as well as a discussion of how m6A modifications facilitate parasite survival through features specific to apicomplexans and kinetoplastids. Beyond parasite epitranscriptomes, this review compares m6A dynamics in host and vector species (humans, flies and mosquitoes), highlighting coevolutionary adaptations. Strikingly, both the parasites and their vectors lack canonical m6A demethylases, implying a largely irreversible, streamlined m6A landscape fine-tuned for synchronized gene regulation. Overall, a mechanistic understanding is emerging of how m6A-modified RNAs and their binding proteins orchestrate RNA processing, translation, and turnover in parasitic protists, revealing an evolutionarily tuned epitranscriptomic system.
    Keywords:  Leishmania; N(6)-methyladenosine (m(6)A); Plasmodium; RNA modification; Toxoplasma; Trypanosoma; YTH-domain protein; coevolution; demethylase; human host; insect vector; methyltransferase
    DOI:  https://doi.org/10.1016/j.bj.2025.100903
  12. Biomolecules. 2025 Jul 22. pii: 1061. [Epub ahead of print]15(8):
    Class IIa HDACs Are Important Signal Transducers with Unclear Enzymatic Activities.
    Claudio Brancolini.
      Class IIa histone deacetylases (HDACs) are pleiotropic regulators of various differentiation pathways and adaptive responses. They form complexes with other co-repressors and can bind to DNA by interacting with selected transcription factors, with members of the Myocyte Enhancer Factor-2 (MEF2) family being the best characterized. A notable feature of class IIa HDACs is the substitution of tyrosine for histidine in the catalytic site, which has occurred over the course of evolution and has a profound effect on the efficiency of catalysis against acetyl-lysine. Another distinctive feature of this family of "pseudoenzymes" is the regulated nucleus-cytoplasm shuttling associated with several non-histone proteins that have been identified as potential substrates, including proteins localized in the cytosol. Within the complexity of class IIa HDACs, several aspects deserve further investigation. In the following, I will discuss some of the recent advances in our knowledge of class IIa HDACs.
    Keywords:  H2BK120ac; H3K27ac; HDAC4; HDAC5; HDAC7; HDAC9; MEF2; enhancers
    DOI:  https://doi.org/10.3390/biom15081061
  13. Cancers (Basel). 2025 Aug 14. pii: 2652. [Epub ahead of print]17(16):
    Regulators of Cancer Progression: Succinylation.
    Jie Gao, Wei Yu.
      Lysine succinylation is a recently discovered post-translational protein modification, the process of which requires the participation of various enzymes. The close association between cancer and protein post-translational modifications (PTMs), such as acetylation and phosphorylation, has been extensively investigated and well-established. In recent years, growing attention has been directed toward the role of succinylation in cancer progression. Accumulating evidence demonstrates that protein succinylation and desuccinylation play critical roles in promoting the development of various cancers, including lung, prostate, and renal cancers. Notably, the primary substrates undergoing succinylation are non-histone proteins. Therefore, elucidating the functions of cancer-related succinylated proteins is essential for identifying novel therapeutic targets. This review comprehensively summarizes current research advances regarding protein succinylation in common cancers and discusses the progress in developing succinylation-targeting drugs. Specifically, we focus on the molecular mechanisms by which succinylation regulates cancer progression, along with the identification of key succinylation sites. Our discussion aims to provide valuable insights for future research and the development of innovative cancer treatments.
    Keywords:  cancer; drug; succinylation; tumor
    DOI:  https://doi.org/10.3390/cancers17162652
  14. Arch Toxicol. 2025 Aug 22.
    Sirtuins as mediators and targets of arsenic toxicity: unraveling signaling pathway crosstalk.
    Sara R El-Mahrouk, Ayman O S El-Kadi.
      Arsenic, a widespread environmental contaminant, threatens millions globally through contaminated water, soil, and food. While arsenic compounds are used to treat acute promyelocytic leukemia, their toxic legacy includes cancers, cardiovascular disease, diabetes, and neurodegeneration, primarily driven by oxidative stress, mitochondrial dysfunction, and epigenetic instability. Sirtuins, a family of NAD⁺-dependent enzymes, are central to cellular defense, orchestrating metabolism, stress resistance, DNA repair, and longevity. Arsenic disrupts sirtuin function, particularly SIRT1, SIRT2, and SIRT3, via microRNA-mediated silencing and post-translational modifications, impairing antioxidant defenses, disturbing energy metabolism, and accelerating cellular injury across organ systems. However, activating sirtuins with agents like resveratrol, metformin, or berberine, as well as through lifestyle interventions, can counteract arsenic toxicity, restore cellular resilience, and provide new therapeutic strategies. This review synthesizes current knowledge on the interplay between arsenic exposure and sirtuin biology, examining how arsenic alters sirtuin expression and activity, the downstream consequences for cellular signaling and organ health, and emerging interventions targeting sirtuin pathways. By bridging molecular insights with translational potential, we highlight the promise of sirtuins as therapeutic targets in combating arsenic toxicity and guide future research directions.
    Keywords:  Arsenic; Arsenic trioxide; FOXO; NF-κB; NRF2; Sirtuins
    DOI:  https://doi.org/10.1007/s00204-025-04158-1
  15. Nat Commun. 2025 Aug 20. 16(1): 7749
    Targeted CRISPR screens reveal genes essential for Cryptosporidium survival in the host intestine.
    Lucy C Watson, Katarzyna A Sala, Netanya Bernitz, Lotta Baumgärtel, Mitchell A Pallett, N Bishara Marzook, Lorian Cobra Straker, Duo Peng, Lucy Collinson, Adam Sateriale.
      The Cryptosporidium parasite is one of the leading causes of diarrheal morbidity and mortality in children, and adolescent infections are associated with chronic malnutrition. There are no vaccines available for protection and only one drug approved for treatment that has limited efficacy. A major barrier to developing new therapeutics is a lack of foundational knowledge of Cryptosporidium biology, including which parasite genes are essential for survival and virulence. Here, we iteratively improve the tools for genetically manipulating Cryptosporidium and develop a targeted CRISPR-based screening method to rapidly assess how the loss of individual parasite genes influence survival in vivo. Using this method, we examine the parasite's pyrimidine salvage pathway and a set of leading Cryptosporidium vaccine candidates. From this latter group, using inducible knockout, we determined the parasite gene known as Cp23 to be essential for survival in vivo. Parasites deficient in Cp23 were able to replicate within and emerge from infected epithelial cells, yet unable to initiate gliding motility which is required for the reinfection of neighbouring cells. The targeted screening method presented here is highly versatile and will enable researchers to more rapidly expand the knowledge base for Cryptosporidium infection biology, paving the way for new therapeutics.
    DOI:  https://doi.org/10.1038/s41467-025-63012-1
  16. Biomedicines. 2025 Aug 01. pii: 1879. [Epub ahead of print]13(8):
    In Vivo Safety and Efficacy of Thiosemicarbazones in Experimental Mice Infected with Toxoplasma gondii Oocysts.
    Manuela Semeraro, Ghalia Boubaker, Mirco Scaccaglia, Dennis Imhof, Maria Cristina Ferreira de Sousa, Kai Pascal Alexander Hänggeli, Anitha Löwe, Marco Genchi, Laura Helen Kramer, Alice Vismarra, Giorgio Pelosi, Franco Bisceglie, Luis Miguel Ortega-Mora, Joachim Müller, Andrew Hemphill.
      Background: Toxoplasma gondii is a globally widespread parasite responsible for toxoplasmosis, a zoonotic disease with significant impact on both human and animal health. The current lack of safe and effective treatments underscores the need for new drugs. Earlier, thiosemicarbazones (TSCs) and their metal complexes have shown promising activities against T. gondii. This study evaluated a gold (III) complex C3 and its TSC ligand C4 for safety in host immune cells and zebrafish embryos, followed by efficacy assessment in a murine model for chronic toxoplasmosis. Methods: The effects on viability and proliferation of murine splenocytes were determined using Alamar Blue assay and BrdU ELISA, and potential effects of the drugs on zebrafish (Danio rerio) embryos were detected through daily light microscopical inspection within the first 96 h of embryo development. The parasite burden in treated versus non-treated mice was measured by quantitative real-time PCR in the brain, eyes and the heart. Results: Neither compound showed immunosuppressive effects on the host immune cells but displayed dose-dependent toxicity on early zebrafish embryo development, suggesting that these compounds should not be applied in pregnant animals. In the murine model of chronic toxoplasmosis, C4 treatment significantly reduced the parasite load in the heart but not in the brain or eyes, while C3 did not have any impact on the parasite load. Conclusions: These results highlight the potential of C4 for further exploration but also the limitations of current approaches in effectively reducing parasite burden in vivo.
    Keywords:  T. gondii; gold-based compounds; in vivo; thiosemicarbazones
    DOI:  https://doi.org/10.3390/biomedicines13081879
  17. Eur J Med Res. 2025 Aug 26. 30(1): 802
    Gene expression profiling in cardiac tissue of mice chronically infected with Toxoplasma gondii: implications for immune response pathways.
    Marzieh Asadi, Mohammad Hossein Banabazi.
      Toxoplasma gondii is a common and opportunistic protozoan in vertebrates. Most cases of infection are asymptomatic, but in individuals with an immune system deficiency, it can cause severe complications. The parasite has the ability to form cysts in the host's heart, brain, and other tissues. Heart tissue damage during toxoplasmosis infection is associated with many complications, such as myocarditis, pericarditis, arrhythmia and heart failure. The parasite can survive and create a chronic form of infection by changing the expression of genes effective in the immune system. Therefore, the present study aims to investigate expression dynamics of candidate genes in the heart tissue of mice infected with the chronic T. gondii strain of Tehran and the pathways involved. After causing toxoplasmosis infection in mice and confirming the infection by MAT, RNA was extracted from the heart tissue of mice and converted into cDNA. Then, real-time PCR was performed to check the expression changes based on the designed primers of the target genes, and pathway analysis was performed. The results of real-time PCR analysis showed that all candidate genes have a higher expression in infected heart tissue compared to non-infected heart tissue. In addition, gene ontology and pathway analysis revealed that the cytosolic DNA-sensing pathway and autoimmune thyroid illness had the most gene participation.
    Keywords:   Toxoplasma gondii ; Chronic infection; Heart; Pathway analysis; Rt-PCR
    DOI:  https://doi.org/10.1186/s40001-025-03088-z
  18. Int J Biol Sci. 2025 ;21(11): 5135-5163
    Roles of SIRT3 in aging and aging-related diseases.
    Yuzi You, Zhong Wang.
      Aging is an inexorable pathophysiological progression characterized by the overwhelming deterioration of tissue integrity and cellular function coupled with increased risks of various aging-related diseases. Demographic shifts toward extended longevity have precipitated a paradigm shift in disease epidemiology, in which neurodegenerative conditions and cardiovascular pathologies now constitute predominant determinants of morbidity and mortality in geriatric populations. These conditions severely erode functional autonomy in aging populations and strain healthcare infrastructures globally. As a principal nicotine adenine dinucleotide-dependent deacetylase within mitochondria, sirtuin 3 (SIRT3) exerts multimodal regulatory effects spanning mitochondrial bioenergetics, oxidative stress, and epigenetic modifications associated with aging. This review summarizes recent discoveries regarding the involvement of SIRT3 in physiological aging and its pathophysiological intersections with major aging-related disorders, providing new insights and ample inspiration for future research aimed at slowing the aging process and improving outcomes in aging-related diseases.
    Keywords:  Aging; Aging-related Diseases; Mitochondria; Neurodegenerative Diseases; SITR3
    DOI:  https://doi.org/10.7150/ijbs.115518
  19. Autophagy. 2025 Aug 28. 1-15
    Deacetylation of ATG16L1 is required for LC3-associated lysosomal microautophagy.
    Qian Wang, Wei Wan, Hongtao Zhang, Tianhua Zhou, Han-Ming Shen, Pingtong Huang, Wei Liu.
      Microautophagy is a selective cellular process in which endolysosomes directly engulf cytoplasmic cargo through membrane invagination. The regulatory mechanisms governing microautophagy remain poorly understood. Here, we identified the deacetylation of ATG16L1 as a critical regulator of LC3-associated lysosomal microautophagy. We demonstrate that ATG16L1 acetylation is dynamically controlled by the acetyltransferase KAT2B and the deacetylase HDAC3. Under lysosomal osmotic stress or glucose deprivation, HDAC3-mediated deacetylation of ATG16L1 within its WD40 domain promotes its interaction with V-ATPase, facilitating ATG16L1 recruitment to lysosomal membranes. While dispensable for macroautophagy, this post-translational modification is essential for LC3 lipidation on lysosomes and enables lysosomal recovery, including the restoration of lysosomal size and degradative capacity following stress. Our results reveal a key role for ATG16L1 deacetylation in driving LC3-associated microautophagy to maintain lysosomal homeostasis.
    Keywords:  ATG16L1; Acetylation; LC3 lipidation; LC3-associated microautophagy; V-ATPase; lysosome
    DOI:  https://doi.org/10.1080/15548627.2025.2551669
  20. Genomics Proteomics Bioinformatics. 2025 Aug 22. pii: qzaf073. [Epub ahead of print]
    Crosstalk Between Lysine Lactylation and Acetylation Regulates Lactate Dehydrogenase in Streptococcus mutans.
    Qizhao Ma, Tao Hu, Yongwang Lin, Jing Li, Jun Huang, Qiong Zhang, Tao Gong, Xuedong Zhou, Lei Lei, Jing Zou, Yuqing Li.
      Post-translational modifications (PTMs) provide essential fine-tuning of protein functions in response to environmental changes. Among the PTMs, lysine acetylation (Kac) and the recently identified lysine lactylation (Kla) play crucial roles in metabolic regulation considering that lactate and acetyl-CoA (Ac-CoA) are generated from pyruvate as the outlet of glycolysis. However, their crosstalk and regulatory mechanisms remain largely unknown, particularly in prokaryotes. Herein, we investigated the intricate interrelation between Kla and Kac in the cariogenic bacterium Streptococcus mutans, a prolific producer of lactate. We conducted a comprehensive profiling of Kla and Kac, observing their wide distribution in glycolytic enzymes. Lactate dehydrogenase (LDH), the terminal enzyme of glycolysis, exhibited dynamic Kla and Kac shifts in line with glycolytic intermediates, where the ratio of Kla to Kac denotes the metabolic influx. Furthermore, ActA was pinpointed as a dual-function acyltransferase catalyzing the Kla and Kac of LDH, both negatively regulating its enzymatic activity. Importantly, the study identifies lysine 307 (K307) on LDH as a critical site, with its acylation significantly altering LDH activity, thereby lactate production and bacterial growth. Our insights into the metabolic regulation mediated by Kla and Kac contribute to the understanding of the metabolism-PTM-metabolism feedback loop, allowing bacteria to fine-tune their metabolism based on the availability of metabolic intermediates.
    Keywords:   Streptococcus mutans ; Glycolysis; Lactate dehydrogenase; Lysine acetylation; Lysine lactylation
    DOI:  https://doi.org/10.1093/gpbjnl/qzaf073
  21. Microbiol Spectr. 2025 Aug 25. e0041625
    Eimeria tenella AMA1 regulates host cell apoptosis through the mitochondrial pathway and the death receptor pathway.
    Xiaoling Lv, Liwen Wang, Sichen Dong, Yutong Yang, Xueqi Zhang, Tong Xu, Kailing Cui, Zhibin Niu, Wenrui Zhao, Rui Bai, Li Zhang, Mingxue Zheng.
      Eimeria tenella can cause severe damage to the organism by regulating host cell apoptosis during parasitic infection. E. tenella apical membrane antigen 1 (EtAMA1) is integral to the invasion process and intracellular survival of E. tenella. To investigate whether EtAMA1 affects host cell apoptosis during parasite infection, we first constructed an EtAMA1 expression system. Western blot and indirect immunofluorescence analyses were performed using polyclonal antibodies against the EtAMA1 protein to evaluate its expression and localization. The impact of EtAMA1 on host cell apoptosis was examined using Annexin V-fluorescein isothiocyanate/propidium iodide fluorescence staining, quantitative PCR, Western blot, transmission electron microscopy, and other methods. The role of EtAMA1 in two apoptotic pathways was further explored by treating host cells with inhibitors targeting either the mitochondrial or death receptor pathways. The findings revealed that EtAMA1, a naturally occurring protein with cell proliferation activity in the parasite, was successfully expressed and was shown to inhibit host cell apoptosis via both the death receptor and mitochondrial pathways. These results suggest that E. tenella regulates host cell apoptosis through EtAMA1.IMPORTANCEE. tenella can regulate host cell apoptosis through EtAMA1. The inhibitory effect of EtAMA1 on apoptosis is achieved through the mitochondrial and death receptor apoptotic pathways. This study can provide new ideas and theoretical support for the research of coccidiostats and vaccines.
    Keywords:  Eimeria tenella; EtAMA1; apoptosis; protein expression
    DOI:  https://doi.org/10.1128/spectrum.00416-25
  22. Sci Rep. 2025 Aug 25. 15(1): 31179
    An efficient machine-learning framework for predicting protein post-translational modification sites.
    Heba M Elreify, Fathi E Abd El-Samie, Moawad I Dessouky, Hanaa Torkey, Said E El-Khamy, Wafaa A Shalaby.
      Post-Translational Modifications (PTMs), particularly lysine 2-hydroxyisobutyrylation (Khib), represent critical regulatory mechanisms governing protein structure and function, with mounting evidence underscoring their important implications in cellular metabolism, transcriptional regulation, and pathological processes. Despite this significance, the experimental identification of Khib sites remains constrained by resource-intensive methodologies and the transient nature of these modifications. To overcome these limitations, we introduce HyLightKhib, a computational framework that leverages Light Gradient Boosting Machine architecture for accurate Khib site prediction. Our approach depends on a hybrid feature extraction strategy, integrating Evolutionary Scale Modeling (ESM-2) embeddings with comprehensive Composition, Transition, and Distribution (CTD) descriptors as well as curated amino acid physicochemical properties for fixed-length peptides of 43 amino acids. The proposed classifier demonstrated considerable performance over contemporary algorithms, including XGBoost and CatBoostimplementations through mutual information-based feature selection optimization. Cross-species validation on diverse organisms including, human, parasite , and rice achieved improved Area Under the Receiver Operating Characteristic Curve (AUC-ROC) scores of 0.893, 0.876, and 0.847, respectively, outperforming existing predictors, such as DeepKhib, and ResNetKhib. HyLightKhib represents an advancement in computational PTM prediction, providing enhanced predictive performance and valuable biological insights with direct implications for functional proteomics and PTM-targeted therapies.
    Keywords:  ESM; LightGBM; Lysine 2-hydroxyisobutyrylation; Machine learning; Mutual information; Post-translational modification; Protein language models
    DOI:  https://doi.org/10.1038/s41598-025-13178-x
  23. Med Oncol. 2025 Aug 27. 42(10): 450
    The role of phosphatidylcholine metabolism in tumors.
    Lulu Li, Yongxiu Huang, Yaoqi Gui, Wenqiong Xiang, Min Yang, Yu Hou, Meixi Peng.
      Phosphatidylcholine (PC), a core component of eukaryotic cell membranes essential for maintaining membrane integrity, has emerged as a critical regulator in oncogenic metabolic reprogramming. Accumulating evidence reveals that dysregulated PC metabolism constitutes a central mechanism driving malignant tumor progression. This review systematically delineates the biosynthetic pathways (Kennedy pathway, PEMT pathway, Lands cycle) and catabolic processes (phospholipase-mediated hydrolysis via PLA2, PC-PLC, and PLD) governing PC homeostasis. We highlight how PC metabolic networks orchestrate pro-tumorigenic effects via multifaceted mechanisms, such as enhancing membrane biosynthesis to support rapid tumor proliferation, activating some proliferative signaling cascades coupled with apoptosis suppression, remodeling the immunosuppressive microenvironment, et al. Notably, small-molecule inhibitors targeting key PC metabolic enzymes (e.g., RSM-932A, FIPI) demonstrate promising anti-tumor efficacy in preclinical models, though therapeutic outcomes are constrained by metabolic plasticity and tumor heterogeneity. By integrating recent advances in lipidomics and spatial metabolomics, this synthesis not only deciphers the evolutionary logic underlying PC-driven oncogenesis but also proposes innovative therapeutic strategies combining metabolic inhibitors with immune checkpoint modulators. Our analysis provides a conceptual framework for targeting phospholipid vulnerabilities in cancer, paving the way for precision oncology applications.
    Keywords:  Metabolic reprogramming; Phosphatidylcholine metabolism; Tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12032-025-03017-4
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