bims-toxgon 2025-09-14 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–09–14
twenty papers selected by
Lakesh Kumar, BITS Pilani

GRA86 Is a Novel Dense Granule Protein Important for Virulence and Bradyzoite Differentiation in Toxoplasma gondii.
TgAP2X-7 is a novel cell cycle-regulated transcription factor that plays an essential role in Toxoplasma tachyzoite propagation.
Sialic Acid-Binding Protein-1 (SABP1) of Toxoplasma gondii: Preliminary Computer-Based Epitope Mapping for Enhanced Vaccine Design.
Development of an in vitro assay using abscisic acid to study Toxoplasma gondii infectivity.
Target compartmentalized metabolism to regulate epigenetics.
Cellular immune response during Toxoplasma gondii infection: deciphering diverse population immune variations.
Fatal Toxoplasma gondii COUG strain infections in southern sea otters (Enhydra lutris nereis): New insight on contributing factors and parasite serotyping.
HDACs in the Brain: From Chromatin Remodeling to Neurodegenerative Disease.
Cryptosporidium parvum protease INS6 plays an important role in parasite proliferation and pathogenicity.
Glycosomal ABC transporter 3 (GAT3) deletion enhances the oxidative stress responses and reduces the infectivity of Trypanosoma cruzi.
Epigenetic Regulation Through Histone Deacetylation: Implications and Therapeutic Potential in Hepatocellular Carcinoma.
Tailored SirReal-type inhibitors enhance SIRT2 inhibition through ligand stabilization and disruption of NAD+ co-factor binding.
SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.
Genetically encoded biosensors of metabolic function for the study of neurodegeneration, a review and perspective.
Lactylation as a metabolic-epigenetic nexus in epilepsy: Mechanisms and therapeutic implications.
Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.
Post-translational modifications at the crossroads of cancer metabolism and immune regulation: therapeutic opportunities and challenges.
Identification of α-Azacyclic Acetamide-Based Inhibitors of P. falciparum Na+ Pump (PfATP4) with Fast-Killing Asexual Blood-Stage Antimalarial Activity by Phenotypic Screening.
Structural and functional characterisation and regulatory mechanisms of SWI/SNF and RSC chromatin remodelling complexes in fungi.
Decoding protein structures with residue interaction networks.

Animals (Basel). 2025 Sep 03. pii: 2591. [Epub ahead of print]15(17):

GRA86 Is a Novel Dense Granule Protein Important for Virulence and Bradyzoite Differentiation in Toxoplasma gondii.

Xiao-Nan Zheng, Jing Li, Xin-Sheng Lu, Hany M Elsheikha, Xing-Quan Zhu.

  Toxoplasma gondii is a globally prevalent parasite capable of establishing lifelong infections, which can have severe consequences in immunocompromised individuals and developing fetuses. GRAs are essential secretory effectors that facilitate nutrient acquisition, modulate host immune responses, and support intracellular survival. In this study, we characterized four putative GRAs (GRA85-88) that co-localize with GRA12 in both tachyzoite and bradyzoite stages. Using CRISPR-Cas9-mediated homologous recombination, we successfully generated knockout strains in both type I RH and type II Pru backgrounds. Phenotypic analysis revealed that GRA85, GRA87, and GRA88 were not individually required for parasite replication, invasion, or virulence. However, deletion of gra86 (PruΔgra86) resulted in a significant reduction in virulence and fewer brain cysts in chronically infected mice, although in vitro growth remained unaffected. Transcriptomic profiling of PruΔgra86 revealed downregulation of bradyzoite-related genes and upregulation of GRAs involved in host interaction. Additionally, in vitro differentiation assays showed impaired bradyzoite development in the absence of GRA86. These findings from murine models and in vitro phenotypic assays highlight GRA86 as a regulator of chronic infection and stage conversion, positioning it as an important player in T. gondii pathogenesis and a promising target for therapeutic intervention.

Keywords:  GRA86; Toxoplasma gondii; bradyzoite differentiation; dense granule protein; subcellular localization; toxoplasmosis; virulence

DOI:  https://doi.org/10.3390/ani15172591
mSphere. 2025 Sep 08. e0043825

TgAP2X-7 is a novel cell cycle-regulated transcription factor that plays an essential role in Toxoplasma tachyzoite propagation.

Padmaja Mandadi, Ramu Anandakrishnan, Rajshekhar Y Gaji.

  Apicomplexan AP2 (ApiAP2) family proteins are a family of transcription factors that are known to regulate gene expression in apicomplexan pathogens, including Toxoplasma. In this study, we focused on TgAP2X-7, a member of the APiAP2 family that is predicted to be essential for Toxoplasma fitness. Endogenous tagging of TgAP2X-7 followed by immunofluorescence analysis revealed that it's a cell cycle-regulated nuclear protein with peak expression in the G1 phase. Since TgAP2X-7 is predicted to be essential for parasite growth, we adopted an auxin-inducible degron (AID) based conditional knockdown approach to understand its function. Phenotypic analysis of the conditional knockdown mutant of TgAP2X-7 showed that the protein is indeed essential for Toxoplasma propagation in vitro, and loss of this transcription factor results in a major defect in invasion and a minor defect in replication. Examination with cell division markers indicated that the absence of TgAP2X-7 results in defects in endodyogeny. Transcriptomic analysis indicated that loss of TgAP2X-7 leads to dysregulation of global gene expression in the parasite, including genes required for host-cell invasion, metabolism, and gene expression. Additionally, Cleavage Under Targets and Tagmentation (CUT&TAG) analysis suggests that TgAP2X-7 likely binds to an 11 bp motif [C/T/G]GCATGCA[G/C/A][C/T/G][G/A] in the parasite genes' promoter region. Together, these findings suggest that TgAP2X-7 is a novel transcriptional regulator in Toxoplasma that governs the expression of genes required for parasite propagation.IMPORTANCEToxoplasma gondii is a protozoan parasite that can cause life-threatening disease in mammals; hence, identifying key factors required for parasite growth and pathogenesis is important to develop novel therapeutics. In this study, we identify and characterize a member of the Apicomplexan AP2 (ApiAP2) family, TgAP2X-7, a developmentally regulated transcription factor. By generating conditional mutant TgAP2X-7, we show that this protein is required for Toxoplasma propagation in vitro, and the absence of this protein results in parasites with significantly reduced competency in invasion, moderate deficiency in replication, and defects in cell division. Importantly, TgAP2X-7-deficient parasites show global changes in gene expression profile, including decreased expression of genes important for Toxoplasma entry into the host cell. Additionally, we identified an 11 bp DNA motif likely recognized by this transcription factor. Hence, this study provides an initial insight into the function of a novel cell cycle-regulated transcription factor essential for Toxoplasma growth.

Keywords:  Toxoplasma gondii; apicomplexan parasites; parasitology; transcription factors

DOI:  https://doi.org/10.1128/msphere.00438-25
J Parasitol Res. 2025 ;2025 9909421

Sialic Acid-Binding Protein-1 (SABP1) of Toxoplasma gondii: Preliminary Computer-Based Epitope Mapping for Enhanced Vaccine Design.

Sarah Gholami, Ali Jebeli Eshrat Abadi, Shadan Ghiabi, Davood Siamian, Hamed Abdollahi, Farane Famili, Ali Yousefi, Hamidreza Majidiani.

  Toxoplasma gondii (T. gondii) infects one third of the human population globally, presenting serious consequences especially in pregnant women or immunosuppressed patients. This study characterized T. gondii sialic acid-binding protein-1 (SABP1) to determine its physicochemical, antigenic, and structural properties as well as immunogenic epitopes using bioinformatics predictions. The amino acid sequence for T. gondii SABP1 was analyzed using ProtParam (physicochemical properties), VaxiJen v2.0 (antigenicity prediction), AllergenFP v1.0 and AllerTOP v2.0 (allergenicity prediction), NetSurfP-6.0 (secondary structure), Robetta (tertiary structure), IEDB, IFNepitope, and IL4pred (immunogenic epitopes). The subcellular prediction was made using signal peptide, transmembrane domain, posttranslational modifications (PTMs) and protein localization). The SABP1 protein (315 residues; 33.73 kDa) possessed antigenicity (0.46), high solubility (0.783), hydrophilicity (GRAVY: -0.335), and an aliphatic index of 69.33. It was shown to be nonallergen. SABP1 is located in the cytoplasm and has no signal peptide or transmembrane domain. Importantly, there were many B- and T-cell epitopes predicted to be immunogenic, which could be beneficial for designing multiepitope vaccines to prevent T. gondii infection. Further validation of these epitopes using wet experiments is needed.

Keywords:  SABP1; Toxoplasma; immunoinformatics; toxoplasmosis; vaccines

DOI:  https://doi.org/10.1155/japr/9909421
Exp Parasitol. 2025 Sep 04. pii: S0014-4894(25)00116-X. [Epub ahead of print]277 109011

Development of an in vitro assay using abscisic acid to study Toxoplasma gondii infectivity.

Tina Wagner, Ildiko Rita Dunay, Arwid Daugschies, Stefanie Wiedmer, Berit Bangoura.

  The common parasite Toxoplasma gondii can infect all warm-blooded animals, including humans. Although most infections in humans remain asymptomatic, clinical toxoplasmosis can develop into a fatal disease. Infections are usually contracted by oral ingestion of tissue cysts or oocysts contained in cat feces. Currently, the mouse bioassay is applied as a final experiment to evaluate meat infectivity. This study aims to establish an alternative cell culture and quantitative polymerase chain reaction (qPCR)-based in vitro infectivity assay for tissue cysts. The phytohormone abscisic acid (ABA) is applied to increase parasite multiplication. A human foreskin fibroblast (HFF) host cell culture was infected with bradyzoites from mouse tissue. Treatment groups included uninfected controls, infected untreated controls, and infected ABA treated groups. The applied ABA concentrations used ranged from 0.2 ng/μl to 20 ng/μl, and ABA incubation times ranged from 2 h to 18 h before ABA removal. At 48 h after infection, T. gondii deoxyribonucleic acid (DNA) in the cell cultures was quantified by qPCR. The results indicate that parasite DNA copy numbers are markedly increased when using ABA at 2 ng/μl for 4-6 h or at 20 ng/μl for 2 h incubation. Our results indicate that this newly established in vitro assay is suitable to determine T. gondii cyst infectivity.

Keywords:  Cell culture; Infection; Meat; Phytohormone; Tissue cyst; Toxoplasma gondii; Zoonosis

DOI:  https://doi.org/10.1016/j.exppara.2025.109011
Trends Endocrinol Metab. 2025 Sep 10. pii: S1043-2760(25)00194-8. [Epub ahead of print]

Target compartmentalized metabolism to regulate epigenetics.

Yun-Zi Mao, Shi-Min Zhao.

Metabolites are donors of epigenetic modifications. Zhao et al. demonstrated that an ELMSAN1 regulated nuclear pyruvate dehydrogenase complex (nPDC) generates an independent nuclear acetyl-CoA pool dedicated to histone acetylation. Disrupting ELMSAN1-nPDC interaction reprograms histone acetylation and impedes tumor progression, highlighting the regulation of epigenetics and cell signaling by targeting compartmentalized metabolism.

DOI: https://doi.org/10.1016/j.tem.2025.09.002
Trends Parasitol. 2025 Sep 11. pii: S1471-4922(25)00230-2. [Epub ahead of print]

Cellular immune response during Toxoplasma gondii infection: deciphering diverse population immune variations.

Junjie Li, Weixin Gao, Zixun Yan, Biqing Yan, Jili Zhang.

  Toxoplasma gondii is a widespread Apicomplexan parasite that affects approximately one-third of the global population. The development and clinical features of toxoplasmosis are closely related to the immune status of the population. While most immunocompetent individuals are asymptomatic after primary acquired infection, immunocompromised patients may develop a range of severe clinical symptoms and complications. In the case of pregnant women the fetuses are at risk of clinical severity following primary infection during pregnancy. This review aims to elucidate the characteristics of immune interaction patterns in individuals with different immune statuses and provide a theoretical basis for more effective, accurate toxoplasmosis treatment strategies. These findings can achieve targeted and precise prevention and control for different groups, effectively guaranteeing public health security.

Keywords:  Toxoplasma gondii; congenital toxoplasmosis; host–pathogen interactions; human immunodeficiency virus; immunology; pregnancy

DOI:  https://doi.org/10.1016/j.pt.2025.08.010
PLoS One. 2025 ;20(9): e0332223

Fatal Toxoplasma gondii COUG strain infections in southern sea otters (Enhydra lutris nereis): New insight on contributing factors and parasite serotyping.

Devinn M Sinnott, Melissa Miller, David Arranz-Solís, Felipe Rodriguez, Jeroen P J Saeij, Francesca Batac, Katherine Greenwald, Colleen Young, Michael D Harris, Mary Gomes, Karen Shapiro.

Fatal infections with the rare COUG strain of the zoonotic parasite Toxoplasma gondii were recently detected for the first time in four southern sea otters (Enhydra lutris nereis) exhibiting severe protozoal steatitis. The objectives of this study were to describe new COUG strain infections in sea otters, investigate the potential contributory role of a recently discovered parasite-infecting narnavirus (Apocryptovirus odysseus) in these infections, assess the potential contribution of vitamin E deficiency in the development of systemic steatitis, and explore the utility of serotyping for strain-specific diagnosis of T. gondii infections in sea otters. Since initial reporting, six additional sea otters died due to fatal COUG strain T. gondii infections. Five animals exhibited lesion patterns resembling the prior case definition including severe, widespread steatitis. The final case died due to severe T. gondii-associated meningoencephalitis with no grossly or microscopically apparent steatitis. In contrast with a recent report utilizing a cougar-derived parasite isolate, A. odysseus RNA was not detected in sea otter-derived COUG strain isolates, suggesting that this narnavirus is not associated with fatal COUG strain infections in sea otters. Serotyping using dense granule (GRA) peptides to distinguish between T. gondii strains infecting sea otters suggests that Type X, Type II, and COUG strains exhibit different peptide-reactivity profiles that may allow them to be distinguished serologically. COUG strain T. gondii infections are an emerging threat to southern sea otter population health, and this strain has the potential to infect other animal and human hosts that share their environment and food sources with sea otters. Additional studies are needed to clarify the environmental sources, epidemiology, pathophysiology, and premortem serodiagnosis of COUG strain T. gondii infections in southern sea otters and other susceptible hosts.

DOI: https://doi.org/10.1371/journal.pone.0332223
Cells. 2025 Aug 29. pii: 1338. [Epub ahead of print]14(17):

HDACs in the Brain: From Chromatin Remodeling to Neurodegenerative Disease.

Luan Pereira Diniz, Pedro de Sena Murteira Pinheiro, Lucas S Franco, Flávia Carvalho Alcantara Gomes.

  Histone deacetylases (HDACs) are key epigenetic regulators that influence chromatin remodeling, gene expression, and cellular plasticity in the central nervous system (CNS). This review provides a comprehensive overview of the classification and functional diversity of HDACs, with particular emphasis on their roles in neural progenitor cells, mature neurons, and glial populations. In neural stem and progenitor cells, HDACs modulate neurogenesis, fate specification, and lineage commitment. In differentiated neurons, HDACs govern synaptic plasticity, memory formation, and survival. In glial cells, including astrocytes and microglia, HDACs orchestrate inflammatory responses, redox balance, and metabolic adaptations. We further examine the dysregulation of HDAC expression and activity in major neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Evidence from human post-mortem brain studies reveals region- and isoform-specific alterations in HDAC expression, which are closely associated with cognitive decline, mitochondrial dysfunction, and neuroinflammation. Preclinical studies support the use of HDAC inhibitors (HDACi) as neuroprotective agents, capable of restoring acetylation homeostasis, reducing neuroinflammation, and improving neuronal function. Given the relevance of HDACi, we summarize current clinical studies assessing the safety of these compounds in the context of tumor biology, as well as their potential future applications in neurodegenerative diseases. Together, this review underscores the dual significance of HDACs as biomarkers and therapeutic targets in the context of CNS disorders.

Keywords:  HDAC inhibitors; epigenetic regulation; glial cells; histone deacetylases; neurodegenerative diseases; neurogenesis; neuroinflammation; synaptic plasticity

DOI:  https://doi.org/10.3390/cells14171338
PLoS Negl Trop Dis. 2025 Sep 12. 19(9): e0013532

Cryptosporidium parvum protease INS6 plays an important role in parasite proliferation and pathogenicity.

Wei He, Zuwei Yang, Jing Wang, Fuxian Yang, Na Li, Rui Xu, Songrong Zeng, Lihua Xiao, Yaoyu Feng, Yaqiong Guo.

BACKGROUND: Cryptosporidium parvum is a common protozoan pathogen responsible for moderate to severe diarrhea in humans and animals. Parasite invasion and egress cause damage to intestinal epithelial cells, which is mediated by a variety of secretory proteins from several unique organelles, such as micronemes. Previous spatial proteomic analysis has identified insulinase-like protease 6 (INS6) as a putative microneme protein in C. parvum. However, the functional contribution of INS6 to Cryptosporidium pathogenicity remains poorly characterized. In this study, we used genetic manipulation techniques to investigate the expression and biological functions of INS6 in C. parvum.
METHODOLOGY/PRINCIPAL FINDINGS: The INS6 gene was tagged and deleted in C. parvum using CRISPR/Cas9 technology. The expression of INS6 was determined by immunofluorescence analysis, ultrastructure-expansion microscopy, and immunoelectron microscopy. Endogenous labelling showed low levels of INS6 expression, which is found in C. parvum micronemes and is absent during the male gamont stage. The effect of INS6 deletion on parasite growth and pathogenicity was assessed in vitro using HCT-8 cultures and in vivo by infection of interferon-γ knockout mice. Deletion of the INS6 gene impaired C. parvum proliferation in vitro and significantly reduced the parasite burden in infected mice. In addition, mice infected with the Δins6 strain showed a significant reduction in the intestinal villus-to-crypt ratio, attenuated body weight loss and increased survival rates, compared to those infected with the INS6-3HA strain.
CONCLUSIONS/SIGNIFICANCE: These results indicate that INS6 protein is involved in C. parvum proliferation and plays a critical role in modulating the pathogenicity of this zoonotic parasite. Deletion of this gene affects the invasion efficiency and pathogenicity of the parasite.

DOI: https://doi.org/10.1371/journal.pntd.0013532
PLoS Negl Trop Dis. 2025 Sep;19(9): e0013479

Glycosomal ABC transporter 3 (GAT3) deletion enhances the oxidative stress responses and reduces the infectivity of Trypanosoma cruzi.

Davi Alvarenga Lima, Héllida Marina Costa-Silva, Karen Stephanie Sebe Albergaria, Juliana Martins Ribeiro, Daniela de Melo Resende, Bruno Alves Santarossa, Daniel Barbosa Liarte, Simone Guedes Calderano, Silvane Maria Fonseca Murta.

Glycosomes, peroxisome-like organelles in Trypanosoma cruzi, contain enzymes involved in various metabolic processes, including glycolysis. Glycosomal ABC transporters (GATs) play a vital role in maintaining metabolic homeostasis by facilitating metabolite exchange between glycosomes and the cytoplasm. GAT3 is a member of the GAT family, which also includes GAT1 and GAT2. GAT3 transcript levels are downregulated in benznidazole-resistant T. cruzi populations; however, its specific functions remain unknown. Therefore, in this study, we generated GAT3 single-knockout and null mutant lines of the T. cruzi Dm28c strain using the CRISPR/Cas9 system to investigate GAT3 roles in parasite biology. RT-qPCR revealed increased GAT2 transcript levels in the GAT3 null mutant line, without any changes in GAT1 levels. Our findings suggest that GAT3 is not essential for T. cruzi survival, as null mutant parasites showed no growth difference compared to the Cas9-expressing controls. Moreover, the GAT3 single-knockout line exhibited increased resistance to benznidazole, whereas the null mutant line exhibited benznidazole susceptibility similar to the control. Furthermore, both GAT3 single-knockout and null mutant lines showed increased tolerance to hydrogen peroxide-induced oxidative stress. In vitro infection assay of L929 murine fibroblasts revealed that the GAT3 null parasites exhibited a significantly lower infection rate and fewer intracellular amastigotes than the controls. Overall, GAT3 is crucial for T. cruzi infectivity and the regulation of oxidative stress responses, playing key roles in the metabolic regulation and pathogenicity of this parasite.

DOI: https://doi.org/10.1371/journal.pntd.0013479
Cells. 2025 Aug 29. pii: 1337. [Epub ahead of print]14(17):

Epigenetic Regulation Through Histone Deacetylation: Implications and Therapeutic Potential in Hepatocellular Carcinoma.

Khulah Sadia, Annalisa Castagna, Silvia Udali, Francesca Ambrosani, Patrizia Pattini, Ruggero Beri, Giuseppe Argentino, Maria Masutti, Sara Moruzzi, Simonetta Friso.

  Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality worldwide. Increasing evidence indicates that epigenetic mechanisms, which are potentially reversible and modifiable by environmental and nutritional factors, play a key role in hepatocarcinogenesis. Histone deacetylases (HDACs) are fundamental epigenetic modulators that regulate chromatin dynamics and ultimately gene transcription with important pathophysiological implications and promising therapeutic perspectives. The role of HDACs is gaining interest for the understanding of HCC development mechanisms and for the potential therapeutic implications of their natural and synthetic inhibitors. This review provides an overview on HDACs classification and their peculiar expression patterns in HCC, with a focus on zinc-dependent histone deacetylases (HDACs). HDAC inhibitors (HDACis), both synthetic and natural-derived compounds, are also discussed for their emerging effects in optimizing the anticancer efficacy of the current therapeutic strategies. Novel dietary-derived and bioactive compounds-based interventions are discussed in the context of HCC management as promising nutri-epigenetic avenues. Targeting HDACs bears a significant therapeutic potential for HCC management while further confirmatory clinical investigation is warranted.

Keywords:  HDACs; combination therapy; epigenetics; hepatocellular carcinoma; histone deacetylases; natural HDAC inhibitors; synthetic HDAC inhibitors

DOI:  https://doi.org/10.3390/cells14171337
RSC Med Chem. 2025 Aug 19.

Tailored SirReal-type inhibitors enhance SIRT2 inhibition through ligand stabilization and disruption of NAD+ co-factor binding.

Ricky Wirawan, Matthias Frei, Anna Heider, Niklas Papenkordt, Florian Friedrich, Thomas Wein, Manfred Jung, Michael Groll, Eva M Huber, Franz Bracher.

Human sirtuin 2 (SIRT2) is an NAD+ dependant enzyme that has been linked to the pathogenesis of various diseases, making it a promising target for pharmaceutical intervention. This study presents a systematic investigation on the inhibitory effects of SIRT2 inhibitors functionalized with diverse electrophilic functional groups. Guided by initial docking studies, we designed and synthesised 14 derivatives of two published potent lead structures 24a and SirReal2. The most potent and subtype selective SIRT2 inhibitor 29 (RW-78) exhibits an IC50 of 26 nM, which outperforms its lead structure 24a (IC50 = 79 nM) by a factor of 3. The increased potency of 29 is explained by halogen-π interactions with SIRT2 residues as visualized by X-ray crystallography. Furthermore, 29 interferes with NAD+ binding, highlighting co-factor displacement as a valid strategy to inhibit SIRT2. Additionally, we showed cellular target engagement via NanoBRET assays in HEK293T cells (EC50 = 15 nM). Altogether our findings provide a deeper insight into the structure-activity relationships of these SirReal-type inhibitors and offer new avenues for optimisation of SIRT2 inhibitors.

DOI: https://doi.org/10.1039/d5md00144g
Aging Cell. 2025 Sep;24(9): e70162

SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.

Marine Barthez, Zehan Song, Yufan Feng, Yifei Wang, Chih-Ling Wang, Danica Chen.

Aging leads to chronic inflammation that is linked to aging-associated conditions and diseases. Multiple immune pathways become activated during aging, posing a challenge to effectively reduce aging-associated inflammation. SIRT2, an NAD+-dependent deacetylase, suppresses several immune pathways that become activated during aging and may represent an attractive target to broadly dampen aging-associated inflammation. Here, we show that SIRT2 deficiency leads to increased inflammation governed by multiple immune pathways and tissue function decline at an old age, while NAD+ boosting with 78c suppresses aging-associated inflammation and improves tissue function. These findings highlight SIRT2 as a master regulator of aging-associated inflammation and support NAD+ boosting as an effective strategy to counteract aging-associated inflammation and tissue function decline.

DOI: https://doi.org/10.1111/acel.70162
Neurophotonics. 2025 Jun;12(Suppl 2): S22805

Genetically encoded biosensors of metabolic function for the study of neurodegeneration, a review and perspective.

Minglei Zhao, Saman Behboudi Tanourlouee, Sean McCracken, Philip R Williams.

  Nervous system tissue is the most metabolically active in the body and neurons are the primary consumers of oxygen and metabolites in nervous tissue. Many processes support neuronal metabolism, and dysregulation of these processes or intrinsic neuronal metabolism is often tied to neurodegenerative diseases. While many techniques are available to query metabolic function and disease (e.g. Seahorse XF, histology, immunostaining), almost all of these approaches are destructive and few offer cellular resolution. However, genetically encoded biosensors can optically measure metabolic features in any tissue with optical access. Biosensors represent an approach to non-destructively monitor metabolic components and regulatory signaling repeatedly over time in intact tissues. In this review, we discuss the application of genetically encoded biosensors that measure metabolites and metabolic processes as applied to studies of neurodegeneration.

Keywords:  genetically encoded biosensors; metabolism; neurodegeneration

DOI:  https://doi.org/10.1117/1.NPh.12.S2.S22805
Neurobiol Dis. 2025 Sep 08. pii: S0969-9961(25)00308-0. [Epub ahead of print] 107091

Lactylation as a metabolic-epigenetic nexus in epilepsy: Mechanisms and therapeutic implications.

Ting Chen, Sha Wen, Ling Gong, Xianfeng Hou, Lian Dong, Ying Bai, Zucai Xu.

  Lactylation is a novel post-translational modification (PTM) mediated by lactate, which dynamically regulates protein functions and gene expression by covalently attaching lactate groups to lysine residues. Recent studies have shown that abnormal lactate metabolism not only contributes to the pathogenesis of epilepsy through microenvironment acidification but also influences neuroinflammation, energy metabolism imbalance, neurotransmitter dysregulation, synaptic plasticity, and epigenetic regulation via lactylation. This positions lactylation as a critical metabolic-epigenetic intersection in the pathological mechanisms of epilepsy. This review systematically summarizes the molecular mechanisms of lactylation and its potential roles in epilepsy, while exploring intervention strategies targeting lactylation to provide new perspectives for epilepsy treatment.

Keywords:  Epilepsy; Lactylation; Metabolic-epigenetic regulation; Neuroinflammation; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.nbd.2025.107091
Sci Adv. 2025 Sep 12. 11(37): eadx6489

Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.

Gujie Wu, Xiaofei Fan, Lin Cheng, Zongwei Chen, Yanjun Yi, Jiaqi Liang, Xiaolong Huang, Na Yang, Jiacheng Yin, Weigang Guo, Yiwei Huang, Shanye Yin.

The interplay between cellular metabolism and immune regulation is central to immune function and disease progression, revealing notable therapeutic opportunities. Upon activation, immune cells undergo metabolic reprogramming to meet heightened demands for energy and biosynthesis, reshaping regulatory networks across epigenomic, transcriptomic, and proteomic layers. Metabolite-derived posttranslational modifications (PTMs) serve as pivotal mechanisms integrating metabolic intermediates with immune signaling pathways. Beyond classical acetylation, diverse nonacetyl PTMs-including lactylation, succinylation, malonylation, palmitoylation, and myristoylation-modify histone and nonhistone proteins, regulating gene expression, protein stability, subcellular localization, enzymatic activity, and protein-protein interactions. Advances in mass spectrometry and bioinformatics now enable precise characterization of these PTMs, uncovering their broad roles in immune regulation. This review summarizes current progress in immunometabolism and explores future directions such as mechanistic studies, combination strategies, and clinical applications. Metabolite-driven PTMs critically connect metabolism to immune regulation, suggesting promising therapeutic approaches for cancer, autoimmune disorders, and inflammatory diseases.

DOI: https://doi.org/10.1126/sciadv.adx6489
Int J Surg. 2025 Sep 09.

Post-translational modifications at the crossroads of cancer metabolism and immune regulation: therapeutic opportunities and challenges.

Jiahua Liu, Jiaao Sun, Chengming Li, Xiu Shan, Yue Feng, Guangzhen Wu.

  Post-translational modifications (PTMs) are chemical modifications that occur on specific amino acid residues after protein biosynthesis, which can affect protein function by altering protein structure, localization and activity, thus expanding protein diversity. Extensive research has demonstrated that PTMs can regulate various metabolic processes, such as glucose and lipid metabolism, as well as immune modulation in tumor cells, thereby promoting tumor initiation, progression, and metastasis. In this article, we systematically review a class of emerging PTMs whose roles in tumor metabolism and immune regulation have gradually been recognized in recent years, including six types: lactylation, palmitoylation, SUMOylation, succinylation, crotonylation, and myristoylation. First, we summarized the occurrence process and biological behavior of these six PTMs. Next, we elaborate the relationship between these PTMs and tumorigenesis and progression from the perspectives of metabolism and immune regulation of tumor cells. Finally, we summarize recent research progress in targeting these six types of PTMs for cancer therapy. This paper aims to provide directions for related researchers, and to provide a theoretical basis for targeting PTMs to treat tumors and make it possible.

Keywords:  cancer; glycolysis; immune regulation; lipid metabolism; post-translational modifications; tumor cell metabolism

DOI:  https://doi.org/10.1097/JS9.0000000000003381
ACS Infect Dis. 2025 Sep 08.

Identification of α-Azacyclic Acetamide-Based Inhibitors of P. falciparum Na+ Pump (PfATP4) with Fast-Killing Asexual Blood-Stage Antimalarial Activity by Phenotypic Screening.

Arturo Casas, Leah S Imlay, Vandana Thathy, Kate J Fairhurst, Adele M Lehane, Aloysus K Lawong, Ioanna Deni, Josefine Striepen, Seungheon Lee, Ashwani Kumar, Chao Xing, Hanspeter Niederstrasser, Bruce A Posner, Benoît Laleu, Susan A Charman, David A Fidock, Joseph M Ready, Margaret A Phillips.

  Malaria treatments are compromised by drug resistance, creating an urgent need to discover new drugs. We used a phenotypic high-throughput screening (HTS) platform to identify new antimalarials, uncovering three related pyrrole-, indole-, and indoline-based series with a shared α-azacyclic acetamide core. These compounds showed fast-killing activity on asexual blood-stage Plasmodium falciparum parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na+ regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the P. falciparum Na+ pump (PfATP4). PfATP4 is localized to the parasite plasma membrane and is essential for maintaining a low cytosolic Na+ concentration. Resistance selections on P. falciparum parasites with two α-azacyclic acetamide analogs identified mutations in PfATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming PfATP4 as the target. PfATP4 is a well-established antimalarial target, and identification of additional PfATP4 inhibitors provides alternative avenues to disrupt its function.

Keywords:  Plasmodium; drug discovery; malaria; pfatp4; resistance; target identification

DOI:  https://doi.org/10.1021/acsinfecdis.5c00436
Mycology. 2025 ;16(3): 988-1010

Structural and functional characterisation and regulatory mechanisms of SWI/SNF and RSC chromatin remodelling complexes in fungi.

Lirong Zhu, Qianqian Liu, Chao Zhao, Meichen Zhu, Xuewei Yang, Jinkui Yang.

  Chromatin remodellers utilise energy generated from ATP hydrolysis to remodel nucleosomes and modulate histones, which are crucial for eukaryotic gene expression and chromatin architecture. The SWI/SNF (switching defective/sucrose non-fermenting) class of ATP-dependent chromatin modifiers in eukaryotes includes two complexes, SWI/SNF and RSC (remodeling the structure of chromatin). In the past 10 years, SWI/SNF and RSC chromatin remodellers have been a focus of research in various organisms, including animals, plants and fungi. In fungi, these two complexes have multiple functions, including roles in regulating hyphal differentiation, sporulation, stress responses, and pathogenicity. In addition to describing conserved structural properties and mechanisms of action, we highlight evidence for sequence and functional divergence in fungal evolution. This review provides a basis for further comparative analyses of the roles and regulatory mechanisms of the SWI/SNF and RSC complexes in taxonomically diverse fungi, laying a good foundation for potential applications in controlling pathogenic fungi.

Keywords:  Chromatin remodelling; SWI/SNF and RSC complexes; fungal pathogenicity; transcriptional regulation

DOI:  https://doi.org/10.1080/21501203.2024.2425170
Trends Biochem Sci. 2025 Sep 05. pii: S0968-0004(25)00195-1. [Epub ahead of print]

Decoding protein structures with residue interaction networks.

Sol C Begue, Emanuela Leonardi, Silvio C E Tosatto.

  The rise of AlphaFold and similar structure predictors has made it possible to determine the 3D structure of almost any protein from its amino acid sequence. Residue interaction networks (RINs), graphs where residues are represented as nodes and interactions as edges, provide a powerful framework for analyzing and interpreting this surge in structural data. Here, we provide a comprehensive introduction to RINs, exploring different approaches to constructing and analyzing them, including their integration with molecular dynamics (MD) simulations and artificial intelligence (AI). To illustrate their versatility, we present different case studies where RINs have been applied to investigate thermostability, allosterism, post-translational modifications (PTMs), homology, and evolution. Finally, we discuss future directions for RINs, emphasizing opportunities for refinement and broader integration into structural biology.

Keywords:  allosterism; artificial intelligence (AI); molecular dynamics simulation; protein structure; residue centrality; residue interaction network (RIN)

DOI:  https://doi.org/10.1016/j.tibs.2025.08.006