bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2025–02–02
sixteen papers selected by
Lakesh Kumar, BITS Pilani
  1. TgGloL is an atypical glyoxalase/VOC domain-containing apicoplast protein that is important for the growth of Toxoplasma.
  2. A novel ENTH domain-containing protein TgTEPSIN is essential for structural maintenance of the plant-like vacuolar compartment and bradyzoite differentiation in toxoplasma gondii.
  3. Characterization of the Activities of Vorinostat Against Toxoplasma gondii.
  4. Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt.
  5. The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?
  6. A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.
  7. Seroprevalence of Toxoplasma gondii in White-Tailed Deer (Odocoileus virginianus) in New York State.
  8. Toxoplasma chitinase-like protein orchestrates cyst wall glycosylation to facilitate effector export and cyst turnover.
  9. Toxoplasma gondii and Rabies-The Parasite, the Virus, or Both?
  10. Tubulin Acetylation Enhances Microtubule Stability in Trabecular Meshwork Cells Under Mechanical Stress.
  11. Trypanosoma cruzi: Genomic Diversity and Structure.
  12. Acetylation modification in the regulation of macroautophagy.
  13. The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.
  14. Metabolic Flexibility and Essentiality of the Tricarboxylic Acid Cycle in Plasmodium.
  15. A promising future for breast cancer therapy with hydroxamic acid-based histone deacetylase inhibitors.
  16. SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.
  1. Mol Biol Cell. 2025 Jan 29. mbcE24090391
    TgGloL is an atypical glyoxalase/VOC domain-containing apicoplast protein that is important for the growth of Toxoplasma.
    Syrian G Sanchez, Esther Pouzet, Loïc Guimbaud, Arnault Graindorge, Laurence Berry, Sébastien Besteiro.
      Glycolysis is a conserved metabolic pathway that converts glucose into pyruvate in the cytosol, producing ATP and NADH. In Toxoplasma gondii and several other apicomplexan parasites, some glycolytic enzymes have isoforms located in their plastid (called the apicoplast). In this organelle, glycolytic intermediates like glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP) are imported from the cytosol and further metabolized, providing ATP, reducing power, and precursors for anabolic pathways such as isoprenoid synthesis. However, GAP and DHAP can spontaneously convert into methylglyoxal, a toxic by-product detoxified by the glyoxalase system, typically involving Glyoxalase-1 (Glo-1) and Glyoxalase-2 (Glo-2). In T. gondii, we identified an atypical protein, TgGloL, containing a Glo-1-like motif but with limited homology to typical Glo enzymes. TgGloL localizes to the apicoplast, and its conditional knockdown impairs parasite growth, indicating its importance. While a specific and direct role for TgGloL in methylglyoxal detoxification within the apicoplast remains unclear, it is crucial for maintaining organelle homeostasis and for overall parasite fitness.
    DOI:  https://doi.org/10.1091/mbc.E24-09-0391
  2. Int J Biol Macromol. 2025 Jan 27. pii: S0141-8130(25)00860-8. [Epub ahead of print]300 140311
    A novel ENTH domain-containing protein TgTEPSIN is essential for structural maintenance of the plant-like vacuolar compartment and bradyzoite differentiation in toxoplasma gondii.
    Kai He, Ruibin Wu, An Yan, Xianyong Liu, Shaojun Long.
      Toxoplasma gondii is an intracellular and parasitic protozoon that harbors specialized cellular structures and molecular mechanisms, including the Plant-like Vacuolar Compartment (PLVAC). The PLVAC performs multifaceted roles in the parasite, contributing to ion homeostasis, proteolysis, pH regulation, and autophagy. Despite significant efforts over the past decade to characterize the PLVAC, the proteins localized to this organelle remain largely unidentified. In this study, we utilized TurboID and genetic engineering techniques to uncover additional biological characteristics and the conferring components in the PLVAC. By exploiting the bait PLVAC proteins cathepsin L (CPL) and chloroquine resistance transporter (CRT), we identified 9 novel PLVAC-associated proteins in the compartment. Further essentiality screening reveals that TgTEPSIN is required for the parasite lytic cycle. Further phenotypic analysis demonstrated the depletion of TgTEPSIN resulted in defects in the maintenance of PLVAC, virulence in mice as well as bradyzoite differentiation. Collectively, our findings broaden the repertoire of PLVAC proteins and provide new insights into the essential component and roles of the PLVAC in T. gondii.
    Keywords:  Bradyzoite differentiation; ENTH domain; PLVAC; Toxoplasma gondii; TurboID; Vesicular transport
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.140311
  3. Int J Mol Sci. 2025 Jan 18. pii: 795. [Epub ahead of print]26(2):
    Characterization of the Activities of Vorinostat Against Toxoplasma gondii.
    Ting Zeng, Chun-Xue Zhou, Dai-Ang Liu, Xiao-Yan Zhao, Xu-Dian An, Zhi-Rong Liu, Hong-Nan Qu, Bing Han, Huai-Yu Zhou.
      Toxoplasma gondii is a globally widespread pathogen of significant veterinary and medical importance, causing abortion or congenital disease in humans and other warm-blooded animals. Nevertheless, the current treatment options are restricted and sometimes result in toxic side effects. Hence, it is essential to discover drugs that demonstrate potent anti-Toxoplasma activity. Herein, we found that vorinostat, a pan-HDAC inhibitor, exhibited an IC50 value of 260.1 nM against the T. gondii RH strain and a selectivity index (SI) > 800 with respect to HFF cells. Vorinostat disrupted the entire lytic cycle of T. gondii in vitro. Proteome analysis indicated that vorinostat remarkably perturbed the protein expression of T. gondii, and proteins involved in "DNA replication" and "membrane" were significantly dysregulated. Furthermore, we found that vorinostat significantly enhanced ROS production and induced parasite apoptosis. Importantly, vorinostat could prolong survival in a murine model. Our findings reveal that vorinostat is effective against T. gondii both in vitro and in vivo, suggesting its potential as a therapeutic option for human toxoplasmosis.
    Keywords:  Toxoplasma gondii; mouse; oxidative stress; vorinostat
    DOI:  https://doi.org/10.3390/ijms26020795
  4. PLoS Pathog. 2025 Jan 27. 21(1): e1012907
    Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt.
    Alyssa Hubal, Anusha Vendhoti, Charles N Shaffer, Sarah Vos, Yalitza Lopez Corcino, Carlos S Subauste.
      The intracellular protozoan Toxoplasma gondii manipulates host cell signaling to avoid targeting by autophagosomes and lysosomal degradation. Epidermal Growth Factor Receptor (EGFR) is a mediator of this survival strategy. However, EGFR expression is limited in the brain and retina, organs affected in toxoplasmosis. This raises the possibility that T. gondii activates a signaling mechanism independently of EGFR to avoid autophagic targeting. We report T. gondii activates Src to promote parasite survival even in cells that lack EGFR. Blockade of Src triggered LC3 and LAMP-1 recruitment around the parasitophorous vacuole (PV) and parasite killing dependent on the autophagy protein, ULK1, and lysosomal enzymes. Src promoted PI3K activation and recruitment of activated Akt to the PV membrane. T. gondii promoted Src association with PTEN, and PTEN phosphorylation at Y240, S380, T382, and T383, hallmarks of an inactive PTEN conformation known to maintain Akt activation. Blockade of parasite killing was dependent of activated Akt. Src knockdown or treatment with the Src family kinase inhibitor, Saracatinib, impaired these events, leading to PTEN accumulation around the PV and a reduction in activated Akt recruitment at this site. Saracatinib treatment in mice with pre-established cerebral and ocular toxoplasmosis promoted PTEN recruitment around tachyzoites in neural tissue impairing recruitment of activated Akt, profoundly reducing parasite load and neural histopathology that were dependent of the autophagy protein, Beclin 1. Our studies uncovered an EGFR-independent pathway activated by T. gondii that enables its survival and is central to the development of neural toxoplasmosis.
    DOI:  https://doi.org/10.1371/journal.ppat.1012907
  5. Biochim Biophys Acta Mol Basis Dis. 2025 Jan 27. pii: S0925-4439(25)00036-5. [Epub ahead of print]1871(3): 167691
    The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?
    Jesline Shaji Tharayil, Amoolya Kandettu, Sanjiban Chakrabarty.
      Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.
    Keywords:  Breast cancer; Glutamine; Glycolysis; Mitochondrial sirtuins; Oxidative phosphorylation; ROS
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167691
  6. Cell Chem Biol. 2025 Jan 21. pii: S2451-9456(25)00002-9. [Epub ahead of print]
    A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.
    Joseph J Smith, Taylor R Valentino, Austin H Ablicki, Riddhidev Banerjee, Adam R Colligan, Debra M Eckert, Gabrielle A Desjardins, Katharine L Diehl.
      Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA metabolism is highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking. Herein, we engineered an acetyl-CoA biosensor from the bacterial protein PanZ and circularly permuted green fluorescent protein (cpGFP). The sensor, "PancACe," has a maximum change of ∼2-fold and a response range of ∼10 μM-2 mM acetyl-CoA. We demonstrated that the sensor has a greater than 7-fold selectivity over coenzyme A, butyryl-CoA, malonyl-CoA, and succinyl-CoA, and a 2.3-fold selectivity over propionyl-CoA. We expressed the sensor in E. coli and showed that it enables detection of rapid changes in acetyl-CoA levels. By localizing the sensor to either the cytoplasm, nucleus, or mitochondria in human cells, we showed that it enables subcellular detection of changes in acetyl-CoA levels, the magnitudes of which agreed with an orthogonal PicoProbe assay.
    Keywords:  acetyl-CoA; biosensor; coenzyme A; metabolism; metabolite; protein engineering
    DOI:  https://doi.org/10.1016/j.chembiol.2025.01.002
  7. Pathogens. 2025 Jan 03. pii: 30. [Epub ahead of print]14(1):
    Seroprevalence of Toxoplasma gondii in White-Tailed Deer (Odocoileus virginianus) in New York State.
    Emily D Ledgerwood, Jason D Luscier.
      The parasitic protozoa, Toxoplasma gondii (T. gondii), is a model organism for one health because of its wide-ranging impacts on humans, wildlife, and domestic animals. Intermediate hosts, including white-tailed deer (Odocoileus virginianus), have been implicated in its maintenance. Prior analysis of Toxoplasma gondii seroprevalence in New York State deer focused on rural areas; however, the high density of domestic cats (Felis catus) in urban areas has been implicated in its spread amongst deer. To address this, the seroprevalence of Toxoplasma gondii was assessed across two suburban and urban areas with known deer overabundance in Onondaga and Suffolk County. Here, domestic cats are the only likely definitive host. Between 2019 and 2023, serum from culled deer was collected, and Toxoplasma gondii seropositivity was determined using the modified agglutination test. Overall seroprevalence was 49.31% (n = 144) but was significantly higher in Onondaga (64%) compared to Suffolk County (36%), despite similarities between these two regions. Deer from Onondaga also had higher antibody titers. These data suggest that although urbanization may be a predictor of Toxoplasma gondii seropositivity in deer, there are additional contributing factors. Overall, this study emphasizes the need for continued surveillance in intermediate hosts and informs public health and wildlife management decisions aimed at limiting the impact of Toxoplasma gondii.
    Keywords:  Felis catus; TgMAT; domestic cat; modified agglutination test; one health; parasite; seropositive; toxoplasmosis; urbanization; wildlife disease
    DOI:  https://doi.org/10.3390/pathogens14010030
  8. Proc Natl Acad Sci U S A. 2025 Feb 04. 122(5): e2416870122
    Toxoplasma chitinase-like protein orchestrates cyst wall glycosylation to facilitate effector export and cyst turnover.
    Yong Fu, Tadakimi Tomita, Louis M Weiss, Christopher M West, L David Sibley.
      Toxoplasma bradyzoites reside in tissue cysts that undergo cycles of expansion, rupture, and release to foster chronic infection. The glycosylated cyst wall acts as a protective barrier, although the processes responsible for formation, remodeling, and turnover are not understood. Herein, we identify a noncanonical chitinase-like enzyme TgCLP1 that localizes to micronemes and is targeted to the cyst wall after secretion. Genetic deletion of TgCLP1 resulted in a thickened cyst wall that decreased cyst turnover, blocked the export of virulence effectors into host cells, and resulted in failure to persist during chronic infection. Genetic complementation with a series of mutants revealed that the GH19 glycosidase domain was crucial for regulating glycosylation of several glycoproteins in the cyst wall. Overall, our findings reveal that TgCLP1 is a multifunctional survival factor that modifies glycoproteins within the cyst wall to modulate export of virulence effectors and regulate turnover of tissue cysts.
    Keywords:  chronic infection; glycobiology; glycosyl hydrolase; virulence
    DOI:  https://doi.org/10.1073/pnas.2416870122
  9. Microorganisms. 2025 Jan 08. pii: 109. [Epub ahead of print]13(1):
    Toxoplasma gondii and Rabies-The Parasite, the Virus, or Both?
    Ragan Wilson, Shannon Caseltine, Edith Will, Jeremiah Saliki, Ruth C Scimeca.
      Toxoplasma gondii is an intracellular protozoan parasite that infects a wide range of vertebrates, including humans. Although cats are the only definitive host, any warm-blooded animal can act as a paratenic host. Throughout the years, this apicomplexan parasite has been studied due to its wide prevalence, zoonotic potential, and host behavioral alterations. Known for its neurological alterations, the rabies virus is one of the most recognized types of zoonosis that, although preventable, still causes deaths in humans and animals worldwide. Due to the overlapping clinical signs of these two pathogens, the objective of this study was to evaluate the prevalence of T. gondii DNA in cerebellum tissue collected for rabies testing; cerebellum tissue from diverse animals is often submitted for this purpose. Between May 2022 and April 2024, we tested 903 cerebellum tissue samples from 22 animal species submitted for rabies testing to the Oklahoma Animal Diagnostic Disease Laboratory. Overall, T. gondii prevalence was 3.96%, with 1.8% found in cats (Felis catus), 1.7% in dogs (Canis familiaris), 0.3% in skunks (Mephitis mephitis), and 0.2% in infected cattle (Bos taurus). Analysis among T. gondii-positive hosts revealed a statistically significant difference in dogs when comparing neutered vs. intact males, with 7.94% (5/63) T. gondii-positive neutered males and 1.61% (3/186) T. gondii-positive intact males (p = 0.02). All the T. gondii-positive samples were negative for rabies. Anamnesis in some of the T. gondii-positive samples included ataxia, aggression, muscle rigidity, lethargy, and seizures, with the latter also described in dogs and aggression in the positive bovine sample. The clinical signs described in the T. gondii-infected hosts can be mistaken for rabies infection; therefore, it is important to consider T. gondii as a differential diagnosis in suspected rabies cases and test for this parasite when negative rabies results are obtained.
    Keywords:  neurological signs; one health; protozoan; virus
    DOI:  https://doi.org/10.3390/microorganisms13010109
  10. Invest Ophthalmol Vis Sci. 2025 Jan 02. 66(1): 43
    Tubulin Acetylation Enhances Microtubule Stability in Trabecular Meshwork Cells Under Mechanical Stress.
    Chien-Chia Su, Vaibhav Desikan, Kevin Betsch, Myoung Sup Shim, Kate E Keller, Paloma B Liton.
       Purpose: To study the roles of tubulin acetylation and cyclic mechanical stretch (CMS) in trabecular meshwork (TM) cells and their impact on outflow pathway physiology and pathology.
    Methods: Primary TM cell cultures were subjected to CMS (8% elongation, 24 hours), and acetylated α-tubulin at lysine 40 (Ac-TUBA4) was assessed by western blotting and immunofluorescence. Enzymes regulating tubulin acetylation were identified via siRNA-mediated knockdowns of ATAT1, HDAC6, and SIRT2. Ac-TUBA4 levels were compared between glaucomatous (GTM) and non-glaucomatous (NTM) TM cells and in frozen sections of human cadaver eyes. The effect of tubulin acetylation on substrate stiffness and cell contractility was evaluated by culturing cells on substrates with varying stiffness and by collagen gel contraction assays, respectively. Microtubule stability was examined by monitoring resistance to nocodazole-induced depolymerization. The in vivo effect on intraocular pressure (IOP) was evaluated following intracameral injections of tubacin in mice.
    Results: CMS induced tubulin acetylation in human TM cells by downregulating the deacetylase HDAC6. Elevated Ac-TUBA4 levels were observed in GTM compared NTM cells and tissues. Tubulin acetylation was not affected by substrate stiffness and did not show a direct effect on TM cell contractility. Tubulin acetylation was found to provide protection against microtubule destabilization induced by nocodazole. Importantly, intracameral injection of tubacin, an HDAC6 inhibitor, significantly lowered IOP in mice.
    Conclusions: Our study highlights a critical role of tubulin acetylation in TM cell response to mechanical stress and its potential impact on IOP regulation. Tubulin acetylation could represent a therapeutic target for glaucoma.
    DOI:  https://doi.org/10.1167/iovs.66.1.43
  11. Pathogens. 2025 Jan 12. pii: 61. [Epub ahead of print]14(1):
    Trypanosoma cruzi: Genomic Diversity and Structure.
    Alfonso Herreros-Cabello, Francisco Callejas-Hernández, Núria Gironès, Manuel Fresno.
      Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease, and one of the most important parasitic diseases worldwide. The first genome of T. cruzi was sequenced in 2005, and its complexity made assembly and annotation challenging. Nowadays, new sequencing methods have improved some strains' genome sequence and annotation, revealing this parasite's extensive genetic diversity and complexity. In this review, we examine the genetic diversity, the genomic structure, and the principal multi-gene families involved in the pathogenicity of T. cruzi. The T. cruzi genome sequence is divided into two compartments: the core (conserved) and the disruptive (variable in length and multicopy gene families among strains). The disruptive region has also been described as genome plasticity and plays a key role in the parasite survival and infection process. This region comprises several multi-gene families, including trans-sialidases, mucins, and mucin-associated surface proteins (MASPs). Trans-sialidases are the most prevalent genes in the genome with a key role in the infection process, while mucins and MASPs are also significant glycosylated proteins expressed on the parasite surface, essential for its biological functions, as host-parasite interaction, host cell invasion or protection against the host immune system, in both insect and mammalian stages. Collectively, in this review, some of the most recent advances in the structure and composition of the T. cruzi genome are reviewed.
    Keywords:  Trypanosoma cruzi; genomic structure; multi-gene families; strains
    DOI:  https://doi.org/10.3390/pathogens14010061
  12. Adv Biotechnol (Singap). 2024 Jun 07. 2(2): 19
    Acetylation modification in the regulation of macroautophagy.
    Li Huang, Hongwei Guo.
      Macroautophagy, commonly referred to as autophagy, is an evolutionarily conserved cellular process that plays a crucial role in maintaining cellular homeostasis. It orchestrates the delivery of dysfunctional or surplus cellular materials to the vacuole or lysosome for degradation and recycling, particularly during adverse conditions. Over the past few decades, research has unveiled intricate regulatory mechanisms governing autophagy through various post-translational modifications (PTMs). Among these PTMs, acetylation modification has emerged as a focal point in yeast and animal studies. It plays a pivotal role in autophagy by directly targeting core components within the central machinery of autophagy, including autophagy initiation, nucleation, phagophore expansion, and autophagosome maturation. Additionally, acetylation modulates autophagy at the transcriptional level by modifying histones and transcription factors. Despite its well-established significance in yeast and mammals, the role of acetylation in plant autophagy remains largely unexplored, and the precise regulatory mechanisms remain enigmatic. In this comprehensive review, we summarize the current understanding of the function and underlying mechanisms of acetylation in regulating autophagy across yeast, mammals, and plants. We particularly highlight recent advances in deciphering the impact of acetylation on plant autophagy. These insights not only provide valuable guidance but also inspire further scientific inquiries into the intricate role of acetylation in plant autophagy.
    Keywords:  Acetylation; Autophagy; Deacetylation; Lysine; Post-translational modification
    DOI:  https://doi.org/10.1007/s44307-024-00027-7
  13. bioRxiv. 2025 Jan 15. pii: 2025.01.15.633193. [Epub ahead of print]
    The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.
    Imad Soukar, Anindita Mitra, Linh Vo, Melanie Rofoo, Miriam L Greenberg, Lori A Pile.
      Epigenetic regulation and metabolism are connected. Epigenetic regulators, like the SIN3 complex, affect the expression of a wide range of genes, including those encoding metabolic enzymes essential for central carbon metabolism. The idea that epigenetic modifiers can sense and respond to metabolic flux by regulating gene expression has long been proposed. In support of this cross-talk, we provide data linking SIN3 regulatory action on a subset of metabolic genes with the cellular response to changes in metabolic flux. Furthermore, we show that loss of SIN3 is linked to decreases in mitochondrial respiration and the cellular response to mitochondrial and glycolytic stress. Data presented here provide evidence that SIN3 is important for the cellular response to metabolic flux change.
    DOI:  https://doi.org/10.1101/2025.01.15.633193
  14. ACS Infect Dis. 2025 Jan 27.
    Metabolic Flexibility and Essentiality of the Tricarboxylic Acid Cycle in Plasmodium.
    Arpitha Suryavanshi, Anusha Chandrashekarmath, Nivedita Pandey, Hemalatha Balaram.
      The complete tricarboxylic acid (TCA) cycle, comprising a series of 8 oxidative reactions, occurs in most eukaryotes in the mitochondria and in many prokaryotes. The net outcome of these 8 chemical reactions is the release of the reduced electron carriers NADH and FADH2, water, and carbon dioxide. The parasites of the Plasmodium spp., belonging to the phylum Apicomplexa, have all the genes for a complete TCA cycle. The parasite completes its life cycle across two hosts, the insect vector mosquito and a range of vertebrate hosts including humans. As the niches that the parasite invades and occupies in the two hosts vary dramatically in their biochemical nature and availability of nutrients, the parasite's energy metabolism has been accordingly adapted to its host environment. One such pathway that shows extensive metabolic plasticity in parasites of the Plasmodium spp. is the TCA cycle. Recent studies using isotope-tracing targeted-metabolomics have highlighted conserved and parasite-specific features in the TCA cycle. This Review provides a comprehensive summary of what is known of this central pathway in the Plasmodium spp.
    Keywords:  Plasmodium; anaplerosis; metabolic flexibility; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1021/acsinfecdis.4c00788
  15. Bioorg Chem. 2025 Jan 20. pii: S0045-2068(25)00049-5. [Epub ahead of print]156 108169
    A promising future for breast cancer therapy with hydroxamic acid-based histone deacetylase inhibitors.
    Tanima Das, Sunandita Bhar, Diya Ghosh, Bikash Kabi, Kanisha Kar, Arpita Chandra.
      Histone deacetylases (HDACs) play a critical role in chromatin remodelling and modulating the activity of various histone proteins. Aberrant HDAC functions has been related to the progression of breast cancer (BC), making HDAC inhibitors (HDACi) promising small-molecule therapeutics for its treatment. Hydroxamic acid (HA) is a significant pharmacophore due to its strong metal-chelating ability, HDAC inhibition properties, MMP inhibition abilities, and more. They were found to increase the efficacy of the approved drugs when used in combination. In this review we presented bioinformatic analysis using available data from the Cancer Genome Atlas and Genotype-Tissue Expression databases, outlined the recent advancements in the application of HA-based HDACi for BC during preclinical investigation and clinical trials, tried to offer the rationale for targeting HDAC in BC with HA-based HDACi, summarised the challenges faced in the successful clinical application of HDACi, and proposed potential strategies to address these challenges, aiming to enhance treatment outcomes in BC. Abbreviations: ABCG2, ATP-binding cassette super-family G member 2; ABC, ATP-binding cassette; ADP, Adenosine diphosphate; APC, Antigen presenting cell; AML, Acute myeloid leukemia; ARH1, Aplysia ras homolog 1; BCRP, Breast cancer resistance protein; BRCA, Breast invasive carcinoma; Bax, B-cell lymphoma associated X; CK5, Cytokeratin 5; CK14, Cytokeratin 14; CK17, Cytokeratin 17; CoRESTMiDAC, Co-repressor for element-1-silencing transcription factor; CRM1, Chromosomal maintenance 1; CTCL, Cutaneous T-cell lymphoma; DNMT, DNA methyltransferase; DFS, Disease-free survival; ER, Oestrogen receptor; EMT, Epithelial-mesenchymal transition; FGFR1, Fibroblast growth factor receptor 1; GEPIA, Gene Expression Profiling Interactive Analysis; GTEx, Genotype tissue expression; HAT, Histone acetylase; HDAC, Histone deacetylase; HDF, Human dermal fibroblast; HER2, Human epidermal growth factor receptor 2; HDLP, Histone deacetylase-like protein; Hsp90, Heat shock protein 90; HSF1, Heat shock factor 1; HeLa, Henrietta Lacks; HER1, Human epidermal growth factor receptor 1; IARC, International Agency for Research on Cancer; IL-10, Interleukin-10; KAP1, KRAB associated protein 1; MDM2, Mouse double minute 2 homolog; MDR, Multidrug resistance; MCF-7, Michigan cancer foundation-7; MEF-2, Myocyte enhancer factor-2MMP- Matrix metalloproteinase; NAD, Nicotinamide adenine dinucleotide; NuRD, Nucleosome remodelling and deacetylation; NF- κ B, Nuclear factor kappa light chain enhancer of activated B cell; NES, Nuclear export signal; NLS, Nuclear localization signal; NCoR, Nuclear receptor corepressor; NCT, National clinical trial; OS, Overall survival; PR, Progesterone receptor; PI3K, Phosphoinositide 3-kinase; PAX3, Paired box gene 3; P-gp, P-glycoprotein; ROS, Reactive oxygen species; SIRT, Sirtuin; SMRT, Silencing mediator for retinoid and thyroid receptor; STAT3, Signal transducer and activator of transcription-3; SAR, Structure-activity relationship; SHP1, Src homology region 2 domain-containing phosphatase 1; SAHA, Suberoylanilide hydroxamic acid; SMEDDS, Self micro emulsifying drug delivery system; TNBC, Triple-negative breast cancer; TSA, Trichostatin A; ZBG, Zinc binding group.
    Keywords:  Breast cancer; Epigenetic dysregulation; HDAC inhibitor; Hydroxamic acid; Pharmacophore; Structure-Activity Relationship
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108169
  16. EMBO J. 2025 Jan 29.
    SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.
    Wei Li, Jing Han, Bin Huang, Tengteng Xu, Yihong Wan, Dan Luo, Weiyao Kong, Ying Yu, Lei Zhang, Yong Nian, Bo Chu, Chengqian Yin.
      Ferroptosis, an iron-dependent form of programmed cell death characterized by excessive lipid hydroperoxides accumulation, emerges as a promising target in cancer therapy. Among the solute carrier (SLC) superfamily, the cystine/glutamate transporter system antiporter components SLC3A2 and SLC7A11 are known to regulate ferroptosis by facilitating cystine import for ferroptosis inhibition. However, the contribution of additional SLC superfamily members to ferroptosis remains poorly understood. Here, we use a targeted CRISPR-Cas9 screen of the SLC superfamily to identify SLC25A1 as a critical ferroptosis regulator in human cancer cells. SLC25A1 drives citrate export from the mitochondria to the cytosol, where it fuels acetyl-CoA synthesis by ATP citrate lyase (ACLY). This acetyl-CoA supply sustains FSP1 acetylation and prevents its degradation by the proteasome via K29-linked ubiquitin chains. K168 is the primary site of FSP1 acetylation and deacetylation by KAT2B and HDAC3, respectively. Pharmacological inhibition of SLC25A1 and ACLY significantly enhances cancer cell susceptibility to ferroptosis both in vitro and in vivo. Targeting the SLC25A1-ACLY axis is therefore a potential therapeutic strategy for ferroptosis-targeted cancer intervention.
    Keywords:  ACLY; Acetylation; FSP1; Ferroptosis; SLC25A1
    DOI:  https://doi.org/10.1038/s44318-025-00369-5
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