bims-toxgon 2026-05-03 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2026–05–03
sixteen papers selected by
Lakesh Kumar, BITS Pilani

Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase.
Phylogenetic study of the protozoan Toxoplasma gondii using cytochrome b and GRA20 genes.
Elucidating binding hot spots and structural stability in sirtuin family proteins for selective inhibitors: a computational approach.
PTP1B in astrocytes drives pathogen-induced neurodegeneration.
Inflammation Drives Phosphorylation and Acetylation of MutS Homolog 3 and Interaction with Cytosolic HDAC6.
Therapeutic potential of HDAC6 inhibitor Tubastatin A in health and diseases: current perspective and future directions.
Revisiting cysteine protease function in Trypanosoma cruzi: implications for parasite egress and differentiation.
Tubulin polyglutamylases TTLL4C and TTLL6B are essential for maintaining cytoskeletal integrity in Trypanosoma brucei.
Adaptation of white adipocytes to cooler temperatures: impacts on energy metabolism and protein acetylation.
Loss of FAM60A disrupts Sin3/HDAC control of the Hippo signaling and promotes oncogenic YAP1 activation.
A High-throughput Fluorescence Polarization Assay for Screening Sirtuin Inhibitors.
Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation.
Glutamine metabolic enzymes: to filament or not to filament?
HDAC Inhibition Induces Transient Phenotypic Inertia in Dormant OCCC Spheroids by Derepression of Cell Cycle Genes.
Dynamic regulation of long non-coding RNAs across asexual and gametocyte development in Plasmodium falciparum.
A Multi-omics PTM Atlas Reveals Key Insights into Metabolic Reprogramming in Colorectal Cancer.

Eur J Med Chem. 2026 Apr 19. pii: S0223-5234(26)00308-9. [Epub ahead of print]313 118863

Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase.

Sasithorn Decharuangsilp, Khuanchai Koompapong, Uthai Arwon, Nongnaput Tuyapala, Marie Hoarau, Lokachet Tanasugarn, Jutharat Pengon, Yuwadee Talawanich, Thanaya Saeyang, Jarunee Vanichtanankul, Yongyuth Yuthavong, Sumalee Kamchonwongpaisan, Aongart Mahittikorn, Darin Kongkasuriyachai.

  Toxoplasma gondii is an obligate intracellular blood and tissue protozoan parasite that infects up to a third of the population worldwide. Several antimalarial drugs, in particular pyrimethamine (PYR), have been used for decades to treat toxoplasmosis. Here, the clinical candidate P218, a potent inhibitor of Plasmodium falciparum dihydrofolate reductase (PfDHFR), and a series of flexible diaminopyrimidine butyrolactone analogues were identified as potent T. gondii dihydrofolate reductase (TgDHFR) inhibitors. The most promising butyrolactone analogue, LA4, displayed an improved TgDHFR inhibition (Ki 1.71 nM), increased antiparasitic properties in vitro (IC50 0.44 nM), and a higher cell selectivity compared to PYR (Ki 13.0 nM, IC50 410 nM) while P218 (Ki 2.19 nM, IC50 370 nM) presented an improved activity with comparable cell selectivity to PYR. The in vivo results against T. gondii RH strain-infected mice showed that P218 reduced parasitic burden in blood whereas LA4 decreased parasite load in peritoneal fluid and blood with an extended mice survival. These findings position butyrolactone LA4 as a new potential for the treatment of acute toxoplasmosis.

Keywords:  Antifolate; Antimalarial; DHFR inhibitor; Flexible diaminopyrimidine; Toxoplasma gondii; Toxoplasmosis

DOI:  https://doi.org/10.1016/j.ejmech.2026.118863
Arch Razi Inst. 2025 Aug;80(4): 1029-1038

Phylogenetic study of the protozoan Toxoplasma gondii using cytochrome b and GRA20 genes.

Bozorgi Soghra, Nabian Sedigheh, Habibi Gholamreza, Afshari Asghar, Shahedi Amin, Nasiri Vahid.

  Toxoplasma gondii is an obligate intracellular protozoan in the phylum Apicomplexa. In addition to humans, toxoplasmosis can cause serious diseases in livestock, leading to significant economic losses. The use of molecular methods with high sensitivity has made it possible to detect and study microorganisms. In this study, the cytochrome b and dense granule 20 (GRA20) genes were utilized for studying Toxoplasma gondii parasites. After collecting 29 animal samples of Toxoplasma gondii, the PCR method was applied to evaluate the presence of GRA20 and cytochrome b genes. The sequences of 11 samples were acceptable and submitted to the NCBI database. MEGA X software was utilized to create the phylogenetic tree. In addition, genetic diversity was studied using the RFLP-PCR assay for the GRA6 gene. Assessment of the bands obtained from PCR showed that the bands related to cytochrome b are found in all species of the Sarcocystidae family, but the bands related to the GRA20 gene are specific to Toxoplasma gondii. In the phylogenetic tree, there was a closer relationship between Iranian isolates of Toxoplasma gondii and the French strain of Toxoplasma gondii. Type I was determined as the genetic type of the protozoan Toxoplasma gondii isolated from Iran. Based on the results, the cytochrome b gene was considered a general gene for recognizing different species of the Sarcocystidae family; however, divergence was seen in the GRA20 gene, which is considered a particular gene for Toxoplasma gondii.

Keywords:   Cytochrome b; Dense granule 20 (GRA20); Phylogenetic analysis; Toxoplasma gondii

DOI:  https://doi.org/10.32592/ARI.2025.80.4.1029
Front Bioinform. 2026 ;6 1786061

Elucidating binding hot spots and structural stability in sirtuin family proteins for selective inhibitors: a computational approach.

Deepak Sharma, Rajiniraja Muniyan.

   Background: The sirtuin (SIRT) family is an NAD+-dependent class III histone deacetylase protein that comprises seven members (SIRT1-7). SIRTs are involved in many cellular pathways, which enable them to act as significant regulators of critical diseases such as cancer, cardiovascular disease, respiratory disease, and diabetes. Despite extensive research conducted to understand SIRT biology, many areas remain unexplored, such as the lack of SIRT isoform selectivity and specificity, restrained potency, limited bioavailability, poor pharmacokinetic and pharmacodynamic properties, and insufficient clinical and preclinical trials. Our study focused on one of the major research gaps, i.e., "lack of SIRT isoform selectivity and specificity," through extensive computational exploration.
Methods: The workflow of our study included molecular docking and molecular dynamics studies to deeply explore conformational dynamics and binding hot spots selective to each SIRT isoform.
Results: As an outcome of our study, we predicted the major flexible regions in each isoform, which may turn out to be selective for each SIRT isoform. Additionally, we predicted SIRT isoform-selective key residues that may regulate the inhibitory potential of SIRT proteins. The primary SIRT isoform-selective residues for SIRT1 were Phe273, Phe297, Tyr280, and His363; for SIRT2, they were Phe119, His187, Val233, Phe235, and Leu239; for SIRT3, they were Leu248, Glu296, and Arg301; for SIRT5, they were Phe70, Tyr102, Gln140, and His158; and for SIRT6, they were Asp61, Trp69, His131, Trp186, Ser214, Arg218, and Leu239.
Conclusion: In this study, we provided a deep cognizance of SIRT biology and a fruitful initiative for in vitro exploration of SIRT-selective inhibitors and an in silico contribution toward their clinical trial success.

Keywords:  conformation dynamics; key residue identification; molecular docking; molecular dynamics; sirtuin

DOI:  https://doi.org/10.3389/fbinf.2026.1786061
J Neuroinflammation. 2026 Apr 29.

PTP1B in astrocytes drives pathogen-induced neurodegeneration.

Zhicheng He, Yihui Xing, Jianqi Gu, Daxiang Xu, Peixuan He, Xiaoqian Lin, Wenjing Cui, Huiling Lv, Haoxuan Ding, Kai Sui, Wenting Hao, Yutao Zheng, Xiaoying Yang, Xufeng Huang, Kun Yin, Cheng He, Kuiyang Zheng, Yinghua Yu, Wei Pan.

  Mounting evidence implicates pathogen infections in the pathogenesis of Alzheimer's disease (AD), yet the cellular mechanisms underlying infection-induced neurodegeneration remain poorly understood. Central to this process is the dysfunction of astrocyte-neuron interactions, which are critical for maintaining neuroinflammatory balance and synaptic homeostasis. Here, we demonstrate that astrocytic protein tyrosine phosphatase 1B (PTP1B) acts as a key regulator of astrocyte reactivity during infection, leading to impaired neuroglial communications and cognitive decline. In a murine model of chronic Toxoplasma gondii (T. gondii) infection, elevated PTP1B levels in astrocytes were closely associated with neuroinflammation and cognitive impairments. Conditional deletion of astrocytic PTP1B or its pharmacological inhibition mitigated neuroinflammation, restored synaptic integrity, and rescued cognitive function. Mechanistically, astrocytic PTP1B induced the polarization of A1-like neurotoxic reactive astrocytes, enhanced glutamate-mediated excitotoxicity, and triggered neuronal senescence, collectively contributing to synaptic damage and cognitive deficits. Notably, elevated levels of PTP1B, GAFP and cellular senescence markers were observed in the serum samples from T. gondii IgG-seropositive individuals and in hippocampal transcriptomes from AD patients, underscoring the translational relevance. Together, our findings reveal that PTP1B-mediated disorder of astrocyte-neuron crosstalk represents a novel mechanism of pathogen-driven neurodegeneration.

Keywords:   Toxoplasma gondii ; A1-like neurotoxic reactive astrocytes; Cognitive impairment; Neuronal senescence; PTP1B

DOI:  https://doi.org/10.1186/s12974-026-03837-9
J Cancer. 2026 ;17(4): 730-739

Inflammation Drives Phosphorylation and Acetylation of MutS Homolog 3 and Interaction with Cytosolic HDAC6.

Stephanie S Tseng-Rogenski, Minoru Koi, John M Carethers.

   Background: MutS Homolog 3 (MSH3), part of the MutSβ DNA mismatch repair complex with MSH2, can reversibly translocate from the nucleus to cytosol via IL-6 signaling, abrogating nuclear MutSβ function and is associated with metastasis and poor patient survival. A polymorphism consisting of deletion of 27-bp proximate to the nuclear localization signal (NLS) (Δ27bpMSH3) allows MSH3 cytosolic retention with IL-6 or oxidative stress. Here, we examined for IL-6-induced post-translational modifications associated with MSH3 cytosolic translocation.
Methods: We utilized MSH3-genotyped colon cancer cell lines after IL-6 treatment to assess post-translational modification of MSH3 via Western blots (WB). We modified sequences within the MSH3-NLS-EGFP reporter construct to assess MSH3 localization via immunofluorescent microscopy and WB after nuclear-cytosolic fractionation. Immunoprecipitation (IP) followed by WB was used to study post-IL-6-induced interactions with MSH3.
Results: MSH3 and Δ27bpMSH3 increased serine phosphorylation after 2 hours followed by tyrosine phosphorylation 18 hours post IL-6 treatment, with Δ27bpMSH3 showing more robust phosphorylation than MSH3 likely due to increased cytosolic translocation. MSH3 cytosolic localization was enhanced by acetylation of lysine residues within MSH3's NLS, specifically at residues K99, K100 and K103. With the observed acetylation control for MSH3 cytosolic localization, IP experiments demonstrate binding of cytosolic-located histone deacetylase 6 (HDAC6) to acetylated Δ27bpMSH3.
Conclusions: Polymorphic MSH3 undergoes serine/tyrosine phosphorylation and NLS acetylation upon IL-6 signaling for its nuclear-cytosolic shift and binds HDAC6 in the cytosol which may contribute to anticipated deacetylation and MSH3 protein stability when separated from MSH2. These modifications might be targeted to regulate MSH3's intracellular localization.

Keywords:  HDAC6; MSH3; MutSβ; acetylation; colorectal cancer; interleukin-6; microsatellite instability; mismatch repair; phosphorylation; post-translational modification

DOI:  https://doi.org/10.7150/jca.131728
Mil Med Res. 2026 ;13(1): 100024

Therapeutic potential of HDAC6 inhibitor Tubastatin A in health and diseases: current perspective and future directions.

Sonu Rajput, Sumeet Kumar Singh, Poonam Yadav, Amit Khurana, Ralf Weiskirchen, Umashanker Navik.

  Histone deacetylase 6 (HDAC6) is a unique, predominantly cytoplasmic enzyme that regulates a broad spectrum of cellular and physiological processes, including cell proliferation, migration, intracellular transport, and differentiation. Its distinct structural configuration, comprising two catalytic deacetylase domains and a zinc finger ubiquitin-binding domain (ZnF-BUZ), enables HDAC6 to deacetylate a variety of non-histone substrates, such as α-tubulin, heat shock protein 90 (Hsp90), cortactin, and peroxiredoxin (Prdx). Furthermore, HDAC6 plays a key role in cellular stress responses and cell survival by facilitating the clearance of misfolded proteins, inducing autophagy, and modulating the unfolded protein response. Despite its cytoprotective roles, HDAC6 has emerged as a therapeutic target due to its involvement in multiple pathological pathways and age-related disorders. Tubastatin A (Tub A), a novel and highly selective HDAC6 inhibitor, demonstrates strong therapeutic potential against neurodegenerative, cardiovascular, autoimmune, metabolic, cancer, and other diseases. Tub A enhances the acetylation of both histone and non-histone proteins, thereby modulating gene expression and diverse cellular processes. It shows pharmacological effects, including anti-inflammatory, neuroprotective, anti-diabetic, anti-obesity, anti-oxidant, and other activities. Moreover, preclinical evidence suggests that Tub A effectively regulates multiple pathological pathways by inhibiting HDAC6, which contributes to ameliorating age-related disorders. Therefore, Tub A represents a promising epigenetic modulator with broad therapeutic relevance. Hence, further comprehensive and large-scale investigations are warranted to elucidate its clinical potential and its roles in disease management, as no clinical data related to Tub A activity are available. This review highlights the therapeutic potential of the selective HDAC6 inhibitor Tub A across various pathological conditions, discusses current preclinical findings, and outlines key challenges and future directions for clinical translation.

Keywords:  Age-related diseases; Cancer; Diabetes; Histone deacetylase 6 (HDAC6); Neurodegenerative diseases; Tubastatin A (Tub A)

DOI:  https://doi.org/10.1016/j.mmr.2026.100024
Microbiol Spectr. 2026 Apr 30. e0413225

Revisiting cysteine protease function in Trypanosoma cruzi: implications for parasite egress and differentiation.

Sara De Grandis, Anne Niggli, Delia Bogenstätter, Gaelle Lentini.

  Chagas disease is a major global health concern affecting millions of people worldwide, with limited therapeutic options in its chronic phase and no prophylactic vaccine. The causative agent, Trypanosoma cruzi, is a unicellular eukaryotic parasite whose life cycle alternates between insect vectors and a wide range of mammalian hosts. In mammalian cells, parasite proliferation depends on iterative cycles of host cell invasion, intracellular multiplication, differentiation, and host cell rupture, releasing hundreds of infective parasites. The mechanisms governing the critical transition from replicative amastigotes to infective trypomastigotes (trypomastigogenesis) and subsequent egress remain poorly understood, largely due to the lack of robust analytical tools. Here, we combined real-time cellular impedance monitoring, stage-specific fluorescent parasites, ultrastructural expansion microscopy, and automated high-content imaging to dissect the late steps of the lytic cycle. We provide quantitative evidence that trypomastigogenesis is temporally coordinated with egress, ensuring the release of fully mature, infective trypomastigotes. Furthermore, we re-evaluate the effect of the cysteine protease inhibitor Z-Phe-Ala fluoromethyl ketone (Z-FA-FMK) at late stages of infection. Our results quantitatively support previous observations that Z-FA-FMK impairs trypomastigogenesis, causing an accumulation of amastigotes and blocking progression to mature trypomastigotes. This arrest delays egress and leads to the release of immature forms, highlighting the essential role of cysteine proteases in parasite differentiation. Together, our work establishes a quantitative framework for dissecting the tightly regulated, multi-step process of lytic cycle termination in T. cruzi and offers a versatile platform for phenotypic screening and drug discovery.
IMPORTANCE: Chagas disease, caused by Trypanosoma cruzi, affects millions worldwide and remains a major global health burden, causing chronic cardiac, digestive, and neurological complications. The disease, disproportionately impacting vulnerable populations, lacks effective treatments for the chronic phase of the disease or a vaccine for its prevention. Parasite replication and host cell exit are tightly linked, but the mechanisms driving the transition from intracellular replicative parasites to infective forms and their subsequent release upon host cell lysis are poorly understood. Using real-time monitoring, fluorescent parasites, and high-resolution imaging, we provide quantitative evidence that cysteine proteases are critical for parasite maturation and that their inhibition uncouples differentiation from egress, leading to the release of immature parasites that are generally considered less infective. These findings reveal fundamental principles of parasite biology, provide a platform for drug discovery, and highlight new avenues to target Chagas disease at a critical stage of infection.

Keywords:  Chagas disease; Trypanosoma cruzi; differentiation; egress; host-pathogen interactions; neglected tropical diseases; protease inhibitors

DOI:  https://doi.org/10.1128/spectrum.04132-25
mSphere. 2026 Apr 30. e0090925

Tubulin polyglutamylases TTLL4C and TTLL6B are essential for maintaining cytoskeletal integrity in Trypanosoma brucei.

Lucas Brehm, Moritz Röder, Stephanie Lamer, Marinus Thein, Andreas Schlosser, Carlo Unverzagt, Klaus Ersfeld.

  Tubulin polyglutamylation is a post-translational modification that modulates microtubule interactions with associated proteins and motor proteins, thereby contributing to the regulation of microtubule dynamics. Although its roles are well established in higher eukaryotes, the functional significance of this modification in protozoan parasites remains poorly understood. In the present study, we characterize two polyglutamylases, TTLL4C and TTLL6B, in the parasite Trypanosoma brucei, a protozoan organism that possesses a subpellicular, nematic array of highly stable microtubules. Using gene knockout and overexpression approaches combined with immunofluorescence, western blotting, and mass spectrometry, we show that TTLL4C functions as an initiator for α-tubulin polyglutamylation, specifically catalyzing monoglutamylation at residue E445. Loss of TTLL4C perturbs posterior cytoskeletal architecture, resulting in blunt cell ends and reduced cell length. By contrast, TTLL6B functions as an elongase with preferential activity on β-tubulin, extending polyglutamate chains after initiation. TTLL6B depletion results in an elongated cell morphology, organelle mispositioning, and delayed cytokinesis. Together, these findings delineate complementary roles of TTLL4C and TTLL6B in maintaining cytoskeletal integrity and cell shape in T. brucei, underscoring the importance of balanced polyglutamylation for morphogenesis and cell cycle progression in kinetoplastids.
IMPORTANCE: Post-translational modifications of microtubules, collectively known as the tubulin code, are increasingly recognized as key determinants in the modulation of microtubule properties. Notably, these modifications have been implicated in the pathogenesis of several diseases, including specific forms of neurodegeneration and ciliopathies. A comprehensive understanding of this regulatory layer is therefore of considerable biological and medical significance. Moreover, the conservation of tubulin post-translational modifications across eukaryotic evolution underscores their fundamental cellular importance. In this study, the protozoan parasite Trypanosoma brucei is used as a model system to examine the functional roles of two microtubule polyglutamylases, TTLL4C and TTLL6B. The findings reveal that these enzymes are essential for maintaining cytoskeletal integrity, cell morphology, organelle positioning, and normal cell growth. Collectively, this work advances our understanding of microtubule regulation and highlights the broader cellular functions governed by tubulin polyglutamylation.

Keywords:  Trypanosoma; cell biology; cytoskeleton; microtubules; post-translational modifications

DOI:  https://doi.org/10.1128/msphere.00909-25
bioRxiv. 2026 Apr 17. pii: 2026.04.14.718465. [Epub ahead of print]

Adaptation of white adipocytes to cooler temperatures: impacts on energy metabolism and protein acetylation.

Hiroyuki Mori, Hadla Hariri, William Moe, Sophia Durham, Yuridia Guzman, Emma Paulsson, Rachel C Simmermon, Parth B Bhanderi, Sydney K Peterson, Mia J Dickson, Charles R Evans, Ormond A MacDougald.

Adipocytes throughout the body reside in distinct thermal environments. Visceral adipocytes within the body core are maintained near 37 °C, whereas those in bone marrow, subcutaneous, and dermal depots occupy cooler regions within the peripheral shell. While brown and beige adipocyte responses to cold stress are well characterized, much less is known about how white adipocytes adapt to moderately reduced temperatures below 37 °C. Our recent work revealed that cultured adipocytes exposed to 31 °C, a temperature representative of distal adipose regions, exhibit enhanced mitochondrial function, including increased substrate oxidation and ATP turnover, yet the mechanisms underlying this upregulation remain unclear. Here we show that adaptation to cool temperatures leads to a widespread decrease in protein acetylation in both undifferentiated and differentiated adipocytes, independent of nutrient status, and that this change is readily reversible upon rewarming. Subcellular fractionation and immunoblotting demonstrate that the hypoacetylation coincides with a compartment-specific enrichment of acetylated proteins within mitochondria, indicating selective remodeling of the mitochondrial acetylome. Transcriptomic and biochemical analyses reveal that these temperature-dependent changes occur without alterations in acetyltransferase or deacetylase expression, NAD⁺ concentration, or acetyl-CoA availability, suggesting regulation through alternative mechanisms affecting acetyl-CoA flux or enzyme activity. Integrative acetyl-proteomic and metabolomic profiling identifies mitochondrial enzymes, including serine hydroxymethyltransferase 2 (SHMT2) and propionyl-CoA carboxylase α (PCCA), whose acetylation correlates closely with changes in associated metabolite pools. Together, these findings establish physiologically relevant cooling as a cell-autonomous regulator of mitochondrial protein acetylation and metabolic adaptation in adipocytes.

DOI: https://doi.org/10.64898/2026.04.14.718465
Cell Death Dis. 2026 Apr 27.

Loss of FAM60A disrupts Sin3/HDAC control of the Hippo signaling and promotes oncogenic YAP1 activation.

Mojnu Miah, Md Nazmul Huda, Md Rafikul Islam, Dayebgadoh Gerald, Sneha Khator, Akash Saha, Jahangir Alam, Janet L Thornton, Allen Gies, Michael A Bauer, Kimberly E Stephens, Bolni M Nagalo, Mohammad A Rahman, Michael P Washburn, Sayem Miah.

FAM60A (also known as SINHCAF) is a subunit of the Sin3/HDAC histone deacetylase complex with established roles in chromatin remodeling, yet its broader cellular functions remain largely undefined. Using immunological, biochemical, CRISPR/Cas9, genomic, and proteomic approaches, we mapped the FAM60A interaction network and its functional impact. We reveal that FAM60A binds directly to HDAC1 to recruit Sin3/HDAC, while a dual-domain architecture mediates additional associations with RNA and DNA-binding proteins. CRISPR/Cas9-mediated HDAC1 knockout abolishes the FAM60A-SIN3A interaction, confirming this dependency. Loss of FAM60A triggers widespread transcriptional rewiring, including downregulation of WWC3-a scaffold for LATS1/2 activation. Consequently, YAP1 dephosphorylation and nuclear accumulation shifted cell-cycle dynamics toward G₁ enrichment and conferred resistance to metabolic stress. Restoration of FAM60A or exogenous WWC3 reactivated Hippo "off" signaling, normalized cell-cycle distribution, and reversed stress resistance. These findings establish FAM60A as a pivotal epigenetic tuner linking histone deacetylation to Hippo pathway regulation and nominate the FAM60A-HDAC1-WWC3 axis as a potential therapeutic target to restore growth control in YAP-driven cancers.

DOI: https://doi.org/10.1038/s41419-026-08778-y
bioRxiv. 2026 Apr 17. pii: 2026.04.06.716694. [Epub ahead of print]

A High-throughput Fluorescence Polarization Assay for Screening Sirtuin Inhibitors.

Kewen Peng, Suryadeep Chakraborty, Yizhen Jin, Hening Lin.

Sirtuins (SIRTs), which remove protein lysine acyl modifications, play crucial roles in diverse cellular processes, including metabolism, gene transcription, DNA damage repair, cell survival, and stress response. Several sirtuins are considered non-oncogene addiction of cancer cells and promising targets for anticancer drug development. High-throughput screening (HTS) methods for sirtuins are critical for the development of potent and isoform-selective sirtuin inhibitors, which are needed to validate the therapeutic potential. Herein, we designed and synthesized a fluorescent polarization (FP) tracer, KP-SC-1. Using this high-affinity tracer, we developed a robust, high-throughput FP competition assay for screening SIRT1-3 inhibitors. The assay was validated by testing known SIRT1-3 inhibitors. The assay can detect NAD + -independent SIRT1-3 inhibitors, as well as NAD + -dependent inhibitors, such as Ex-527 and TM. Finally, our assay showed satisfactory stability and outstanding performance in a pilot library screening. Compared to previous assays, the FP assay uses much less SIRT1-3 enzymes, a feature important for high-throughput library screening. We believe that the FP assay developed here will accelerate the discovery and development of SIRT1-3 inhibitors.

DOI: https://doi.org/10.64898/2026.04.06.716694
Nat Neurosci. 2026 Apr 30.

Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation.

Sami Sauma, Stephanie Stransky, Ipek Selcen, Simone Sidoli, Rinat Abzalimov, Ye He, Patrizia Casaccia.

How it is determined whether postnatal oligodendrocyte progenitor cells (OPCs) will survive, proliferate or differentiate remains unclear. Here we suggest that temporal and brain regional fluctuations of glucose, concomitant with changes in vascularization, modulate OPC population dynamics. We found that regions with high glucose levels exhibited greater OPC proliferation and histone acetylation than regions with low glucose and that this was mediated by the enzyme ATP-citrate lyase (ACLY), which converts glucose-derived citrate to acetyl-CoA. Mice with Acly deletion in OPCs showed a transient hypomyelination phenotype resulting from decreased OPC numbers, whereas their differentiation into oligodendrocytes (OLs) proceeded due to compensatory upregulation of enzymes responsible for extranuclear generation of acetyl-CoA from alternative metabolic substrates. Therefore, OPCs rely on ACLY-dependent nuclear acetyl-CoA from glucose-derived citrate, to regulate proliferation, whereas OLs rely on extranuclear acetyl-CoA from other sources for myelin formation. This suggests a metabolic regulation of OL lineage cell population dynamics.

DOI: https://doi.org/10.1038/s41593-026-02263-7
Biochem Soc Trans. 2026 Apr 29. 54(4): 375-392

Glutamine metabolic enzymes: to filament or not to filament?

Raquel A C Machado, Ivan Rosa E Silva, Thaís Fontes-Milz, Yuan Chang-Halabi, Jhon A Vargas, Andre L B Ambrosio, Sandra M G Dias.

  The self-assembly of metabolic enzymes into filaments and other supramolecular structures is well-documented in bacteria and yeast but remains largely unexplored in mammalian cells. Enzyme filamentation is thought to play a crucial role in regulating metabolic networks by modulating enzymatic activity in response to cellular demands. Studies in yeast suggest that filament-forming enzymes are often positioned at key junctions of metabolic pathways, enabling dynamic activation or inactivation during growth or stress and directing metabolic flux accordingly. While this mechanism appears to be broadly conserved across species, the structural and functional characterization of human homologs of filamentous enzymes remains limited. In the present review, we focus on the glutamine metabolic pathway, highlighting enzymes known to form large self-assemblies in cells and examining the few cases where structural insights are available. Finally, we discuss the broader implications of metabolic enzyme filamentation in mammalian cells, underscoring its potential as an emerging area of research.

Keywords:  glutamine pathway; metabolic enzyme filamentation; supramolecular structure

DOI:  https://doi.org/10.1042/BST20253136
Cells. 2026 Apr 10. pii: 673. [Epub ahead of print]15(8):

HDAC Inhibition Induces Transient Phenotypic Inertia in Dormant OCCC Spheroids by Derepression of Cell Cycle Genes.

Sylvia Cheng, Bart Kolendowski, Yudith Ramos-Valdes, Trevor G Shepherd, Gabriel E DiMattia.

  Multicellular cancer cell aggregates, termed spheroids, are anoikis-resistant, avascular, heterogeneous structures responsible for transcoelomic metastasis of ovarian clear cell carcinoma (OCCC). OCCC is a rare subtype of ovarian cancer with high ARID1A gene mutation rates, resulting in genome-wide changes to H3K27Ac levels and histone deacetylase (HDAC) function. Our study investigated the utility of HDAC inhibitor (HDACi) treatment and H3K27Ac dynamics in OCCC spheroids. By comparing KOC-7c and 105C OCCC cell lines, which have opposing abilities to proliferate as spheroids, we revealed that KOC-7c and 105C spheroids differentially regulated H3K27Ac levels, which correlated with the sensitivity of KOC-7c and the resistance of 105C spheroids to H3K27Ac-altering HDACi treatment. RNA-seq of Entinostat-treated versus vehicle-treated spheroids resulted in a dramatic change in the 105C spheroid transcriptome such that it more closely resembled the proliferative KOC-7c transcriptome over the short term. Comparative pathway analysis identified preferential de-repression of a G2/M checkpoint gene program in 105C spheroids upon Entinostat treatment when compared directly to the KOC-7c spheroids. Our results suggest that the utility of HDACi in OCCC is highly context-dependent.

Keywords:  ACY1215; Entinostat; HDAC inhibitor; cancer; cell line; clear cell; dormancy; ovarian; spheroid

DOI:  https://doi.org/10.3390/cells15080673
bioRxiv. 2026 Apr 18. pii: 2026.04.15.718799. [Epub ahead of print]

Dynamic regulation of long non-coding RNAs across asexual and gametocyte development in Plasmodium falciparum.

Janne Grünebast, Ritwik Singhal, Sophie Olson, Robin Bromley, Sachie Kanatani, Katie Ko, Julie Dunning Hotopp, Photini Sinnis, Manuel Llinás, David Serre.

Long non-coding RNAs (lncRNAs) are critical regulators of gene expression in eukaryotes. Short reads from Illumina sequencing, reverse transcriptase artefacts, and incomplete second-strand degradation in strand-specific cDNA libraries hamper genome-wide identification of lncRNAs, especially in gene-dense genomes such as Plasmodium . Here, we integrated long-read Oxford Nanopore Technology direct RNA sequencing, ribosome profiling, and single-cell transcriptomics to generate a robust and stage-specific characterization of P. falciparum lncRNAs. We generated comprehensive annotations of lncRNAs expressed in both asexual and sexual blood stages and confirmed their non-coding nature using ribosome profiling. Most lncRNAs showed pronounced stage-specific expression and appeared to be particularly abundant in mature gametocytes. Single-cell RNA sequencing revealed differential expression of many lncRNAs in female and male gametocytes, suggesting important roles in gametocytogenesis and transmission. Many lncRNAs are located antisense to protein-coding genes and are co-expressed with their sense mRNA, possibly from putative bidirectional promoters, while others overlap mRNA coding sequences or 3' untranslated regions and showed negatively correlated expression patterns. Overall, our study shows the prevalence of P. falciparum lncRNAs and highlights their possible roles in controlling the regulation of gene expression, particularly during gametocytogenesis.

DOI: https://doi.org/10.64898/2026.04.15.718799
Cancer Genomics Proteomics. 2026 May-Jun;23(3):23(3): 448-469

A Multi-omics PTM Atlas Reveals Key Insights into Metabolic Reprogramming in Colorectal Cancer.

Tianyuan Li, Jingjing Dong, Yujie Zhang, Erjiao Hao, Jie DU, Min Feng, Feng Zhu, Juan Qin, Wei Zhang, Yong Dai.

   BACKGROUND/AIM: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with limited effective targeted therapies. Metabolic reprogramming is a hallmark of cancer, and post-translational modifications (PTMs), such as phosphorylation, ubiquitination, and malonylation, play critical roles in regulating metabolic pathways. However, their contribution to metabolic reprogramming in CRC remains unclear.
MATERIALS AND METHODS: Phosphorylation, ubiquitination, and malonylation were analyzed in paired CRC and adjacent normal tissues using high-resolution mass spectrometry. Differential PTM patterns were analyzed, followed by identification of key regulatory enzymes and modification sites. Functional enrichment, protein-protein interaction (PPI) networks, and multi-omics integration were used to explore PTMs' role in CRC metabolism.
RESULTS: We identified 59 differential phosphorylation sites, 263 ubiquitination sites, and 64 malonylation sites in CRC tissues compared with normal tissues, affecting key metabolic enzymes such as IDH1, LDHA, PDHA1, and GAPDH. Altered ubiquitination of IDH1 and LDHA may be associated with changes in protein stability and activity. Phosphorylation of PDHA1 correlated with its modified levels, potentially promoting glycolytic preference in CRC, while increased malonylation of GAPDH may influence its enzymatic activity and glycolytic flux. Protein interaction and pathway analyses further revealed a PTM-regulated metabolic network, suggesting a potential role of PTMs in CRC metabolic reprogramming.
CONCLUSION: This study suggests that PTMs may contribute to metabolic reprogramming in CRC by modulating key metabolic enzymes, including IDH1, LDHA, PDHA1, and GAPDH. These modifications may influence glycolysis and energy metabolism, highlighting PTM-regulated pathways as potential therapeutic targets. The integrated PTM atlas offers insights into the metabolic landscape of CRC.

Keywords:  Colorectal cancer; PTM; malonylation; metabolism; phosphorylation; ubiquitination

DOI:  https://doi.org/10.21873/cgp.20584