Search Results (3,150)

Lactylation is an emerging lactate-derived post-translational modification that may link tumour metabolic reprogramming, epigenetic regulation and DNA damage repair. Enhanced glycolysis and lactate accumulation are common in many tumours, and lactate has been reported to induce histone and non-histone lactylation in specific experimental contexts. Recent studies suggest that lactylation is associated with several DNA repair pathways, including base excision repair/single-strand break repair, nucleotide excision repair, homologous recombination and non-homologous end joining, and may contribute to therapy resistance in selected cancer models. Specifically, XRCC1 lactylation has been reported to promote nuclear translocation and repair activity in glioblastoma models; H4K12 lactylation has been linked to PARP inhibitor resistance through RAD23A activation in ovarian cancer models; and BLM lactylation has been associated with enhanced homologous recombination repair in bladder cancer models. Lactylation of NBS1, RAD51 and XLF has also been implicated in DNA repair regulation in specific experimental systems, although some mechanistic links are inferred from pathway activation or functional rescue experiments rather than directly demonstrated across multiple tumour types. These findings suggest that lactylation may modulate DNA repair and therapeutic response in a context-dependent manner. Targeting lactate metabolism, transport and lactylation regulators, including LDHA, MCT1/4, ACAT1, AARS1 and GCN5, or using site-specific lactylation-inhibiting peptides may improve chemotherapy and PARP inhibitor efficacy, but clinical translation remains limited by heterogeneity, metabolic plasticity, toxicity and insufficient validation. Full article

Regulated cell death is essential for tissue homeostasis, immune defense, and disease progression, yet the lipid-based regulatory mechanisms that coordinate cell death signaling remain incompletely understood. Protein palmitoylation is a dynamic and reversible lipid post-translational modification that controls protein membrane association, trafficking, stability, and signaling complex assembly. This review summarizes the regulatory roles of palmitoylation and depalmitoylation in major forms of regulated cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-related cell death. Particular attention is given to representative palmitoylated substrates, including Fas cell surface death receptor (Fas), receptor-interacting protein kinase 1 (RIPK1), NLR family pyrin domain containing 3 (NLRP3), gasdermin D (GSDMD), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), autophagy-related 16 like 1 (ATG16L1), and Beclin1. These substrates illustrate how palmitoylation links membrane organization, metabolic status, inflammatory signaling, and cell fate decisions. Disease-oriented evidence further indicates that dysregulated palmitoylation contributes to cancer, neurodegenerative diseases, and inflammatory or immune-related disorders by modulating cell death resistance, inflammatory amplification, immune evasion, or impaired proteostasis. Current challenges include limited quantitative information on palmitoylation dynamics, incomplete evidence for some enzyme–substrate relationships, and insufficient distinction between disease-driving and secondary palmitoylation events. Targeting zinc finger Asp-His-His-Cys (zDHHC) palmitoyl acyltransferases, depalmitoylating enzymes, or specific palmitoylated substrates may provide new therapeutic opportunities. Overall, this review positions protein palmitoylation as a dynamic molecular switch linking lipid metabolism, membrane signaling, regulated cell death, and disease remodeling. Full article

The integration of artificial intelligence (AI) into the life sciences has accelerated significantly between 2022 and 2026, accompanied by global investment exceeding USD 100 billion and widespread expectations of a transformative impact in drug discovery. Despite these advances, the extent to which AI has improved clinical outcomes remains unclear. This study presents a structured narrative review evaluating the economic, technical, clinical, and regulatory dimensions of AI adoption in drug discovery. Current evidence indicates that clinical attrition rates remain high, with approximately 90% of drug candidates entering clinical development failing to achieve regulatory approval. Although AI systems such as AlphaFold have achieved high structural prediction accuracy, with predicted local distance difference test (pLDDT) scores exceeding 90 for well-structured proteins and root mean square deviation (RMSD) values comparable to experimental methods, limitations persist in modelling protein dynamics, post-translational modifications, and protein–ligand interactions. Clinical case studies demonstrate that while AI can accelerate early-stage discovery timelines, these advantages do not consistently translate into improved late-stage success rates. Furthermore, reproducibility challenges, limited data transparency, and regulatory gaps continue to constrain reliable implementation. These findings suggest that AI in drug discovery is currently in a transitional phase characterised by high investment but limited validated clinical impact. Future progress will depend on strengthening validation frameworks, improving data sharing practices, and aligning regulatory standards with real-world clinical performance. Full article

Ubiquitin-like proteins (UBLs) such as SUMO, NEDD8, ISG15, FAT10, and UFM1 are proteins that share structural similarities to ubiquitin. Like ubiquitin, they function as protein modifiers, catalyzing modifications through a conserved enzymatic cascade of E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. In doing so, UBLs regulate a diverse set of cellular processes, including stress response, antiviral activity, nuclear transport, cancer development, and autophagy. In recent years, the roles of UBLs during pathogenic bacteria infection have gained attention, although much still remains elusive. This review describes current findings related to UBL systems in the context of pathogenic bacteria infection, focusing on NEDD8, ISG15, FAT10, and UFM1. Specifically, we look at how the host UBL system responds to bacterial infection by inducing the host’s defense system, and how pathogenic bacteria manipulate the host UBL system to ensure successful infection. Full article

The cryopreservation of pre-implantation embryos has become routine in medically assisted reproduction (MAR), and the proportion of frozen embryo transfers has steadily increased in recent years. Because cryopreservation through either slow-cooling protocols or ultra-rapid vitrification requires potentially cytotoxic cryoprotective agents to prevent uncontrolled and detrimental ice crystal formation, the safety of these procedures must be carefully considered. Evidence from human epidemiological studies, including retrospective and prospective controlled studies, and data from national patient registries indicate that children born after frozen embryo transfer have a higher birth weight than those born after spontaneous conception and have an increased risk of rare genomic imprinting disorders, such as Beckwith–Wiedemann, Silver–Russell, or Prader–Willi syndrome. Encompassing not only reversible DNA methylation patterns established during gametogenesis, but also the timed abundance and availability of transcripts and proteins required to establish or maintain epigenetic marks throughout development and differentiation, as well as persistent or transient post-translational histone modifications and non-coding RNAs, the epigenome may be particularly sensitive to cryopreservation. Importantly, epigenetic regulation is highly complex. Alterations of the epigenome at any developmental stage are often not monocausal, do not necessarily result in immediate disturbances in the pre-implantation embryo, and are unlikely to operate through simple all-or-nothing mechanisms; however, they may have long-lasting effects at later developmental stages. To make matters even more complex, differences between species in terms of epigenetic regulation or lineage differentiation are well known and translation from animal model systems to humans must be considered with caution. More recently, epigenetic regulation by non-coding RNAs has also come into focus, as these molecules are crucial, either directly or indirectly, for gene expression, translation, and protein biosynthesis during development. Therefore, assessing potential adverse effects of cryopreservation on the entire epigenome remains a major challenge, particularly because little is known about indirect factors, such as post-translational histone modifications and non-coding RNAs. In this review, we focus on the potential influence of the cryopreservation of pre-implantation embryos on the epigenetic profile in humans and animals. Specifically, we consider DNA methylation of imprinted genes and global DNA methylation; post-translational histone modifications; the abundance and availability of transcripts and proteins required to establish, maintain, or protect epigenetic patterns; and the presence of non-coding RNAs involved in epigenetic control. Full article

O-linked glycosylation comprises distinct regulatory systems, including secretory-pathway mucin-type O-GalNAc glycosylation and intracellular O-GlcNAcylation. These modifications both target serine/threonine residues but differ in glycan structure, cellular compartment, enzymatic machinery, and biological function. This narrative review was based on targeted searches of PubMed, Web of Science, and related literature using keywords related to O-glycosylation, O-GalNAc glycosylation, O-GlcNAcylation, immune regulation, cell signaling, glycoproteomics, and congenital disorders of glycosylation (CDG). We summarize evidence that mucin-type O-glycosylation regulates receptor behavior, cell adhesion, immune checkpoints, immunoglobulin function, antigen recognition, and pathogen–host interactions, whereas O-GlcNAcylation mainly modulates intracellular signaling, transcriptional control, stress responses, post-translational modification crosstalk, and innate immune pathways. We also discuss how glycosylation defects, including CDG and selected O-linked glycosylation disorders, connect genetic variation with disease phenotypes. Recent advances in site-specific glycoproteomics, O-glycoprotease-assisted workflows, LC–MS/MS-based glycopeptide analysis, and spatial or temporal profiling have improved mechanistic interpretation but still face limitations in site localization, structural resolution, and functional validation. Overall, the evidence supports the hypothesis that distinct O-linked glycosylation systems act through different molecular mechanisms but converge on signaling regulation, immune homeostasis, and disease susceptibility. Full article

This review argues that protein lactylation—a lactate-driven posttranslational modification—serves as the long-sought molecular bridge that coordinates these two hallmarks in gastric cancer (GC). Far from being a passive metabolic byproduct, lactylation operates as a central molecular hub with a dual function: intracellularly, it directly drives malignant phenotypes by modifying key oncoproteins such as YAP and metabolic enzymes; extracellularly, it remodels the tumor immune microenvironment by polarizing tumor-associated macrophages toward an immunosuppressive M2 phenotype, upregulating PD-L1 expression, and impairing CD8⁺ T-cell function. We propose that these two arms constitute a self-reinforcing metabolic–epigenetic–immunological circuit, wherein lactylation both originates from and perpetuates the Warburg effect, creating a vicious cycle that sustains malignancy and immune evasion. This framework positions lactylation not merely as a mechanistic detail, but as a unifying principle that integrates metabolic reprogramming, epigenetic regulation, and immune suppression in GC. We critically evaluate the current landscape of lactylation “writers,” “erasers,” and “readers”; highlight the translational potential of targeting this pathway; and identify the conceptual and technical bottlenecks that must be overcome—including the lack of causality in current studies, the absence of specific research tools, and the unresolved heterogeneity of lactylation across cell types and disease stages. By reframing lactylation as an actionable hub rather than a downstream consequence, this review provides a roadmap for advancing lactylation-based precision medicine in GC. Full article

Heart failure (HF) remains a major cause of morbidity and mortality despite substantial therapeutic progress, and important phenotype-specific treatment gaps persist. Protein S-nitrosylation (SNO) is a reversible cysteine-centered post-translational modification (PTM) whose reported associations with selected HF-relevant contexts, including vascular–endothelial dysfunction, mitochondrial–energetic remodeling, Ca²⁺-handling abnormalities, and selected receptor- or stress-related signaling observations, are supported to varying degrees. In this review, we evaluate reported mechanisms that may regulate cardiac SNO and define the evidentiary boundaries that constrain interpretation across HF-relevant settings. Available studies suggest that altered SNO homeostasis is associated with selected HF-related processes, but the strength of support varies substantially across targets, phenotypes, and disease contexts. Many mechanistic observations derive from animal models, cultured systems, donor-based perturbations, or non-HF settings. These should, therefore, be interpreted as hypothesis-generating rather than as established mechanisms in human HF. We accordingly distinguish findings supported by human HF tissue or HF-relevant in vivo evidence from more preliminary observations and highlight the need for human, site-resolved, and, where feasible, quantitatively grounded datasets. Future studies should prioritize stronger tissue anchoring, better integration of circulating and myocardial readouts, and closer alignment between mechanistic claims and the strength of the supporting evidence. Full article

Clear cell renal cell carcinoma (ccRCC) is characterized by a complex molecular landscape driven by recurrent genetic alterations. While genomic and transcriptomic profiling have identified core drivers, they often fail to provide robust biomarkers due to the significant decoupling of mRNA and protein levels, as well as the critical role of post-translational modifications in tumor biology. This review synthesizes current evidence from landmark proteogenomic initiatives, such as the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and independent multi-omic studies. It evaluates the integration of genomic, transcriptomic, and proteomic data to map metabolic reprogramming, signalling pathway activity, and chromatin-level alterations in ccRCC. Proteogenomic analyses reveal that protein-level data provide a functional perspective that is missing from sequencing alone, specifically identifying suppressed oxidative phosphorylation, enhanced glycolysis, and the activation of the PI3K/AKT/mTOR cascade, independent of genetic mutations. Furthermore, proteogenomics has defined novel molecular subtypes and individual protein biomarkers, such as UCHL1 and p-mTOR, which correlate more accurately with clinical outcomes and therapeutic responses than their transcriptomic counterparts. Proteogenomics is a crucial tool for refining disease taxonomy and identifying novel therapeutic vulnerabilities in ccRCC. By bridging the gap between genotype and functional phenotype, this integrated approach facilitates more precise risk stratification and accelerates the development of personalized medicine through better-informed selection of targeted and immune-based therapies. Full article

Ubiquitous environmental endocrine-disrupting chemicals (EDCs), including bisphenols, phthalates, and heavy metals, pose a severe and persistent threat to mammalian reproductive health worldwide. Oxidative stress acts as the pivotal mediator which drives epigenetic dysregulation in germ cells upon EDC exposure, including aberrant DNA methylation, abnormal histone post-translational modifications and dysregulated non-coding RNA networks. EDC-induced oxidative stress damages endogenous antioxidant defense systems and inactivates key epigenetic regulators, forming a self-reinforcing cycle of redox imbalance and epigenetic dysregulation, which ultimately leads to impaired gametogenesis, reduced fertility, and transgenerational reproductive abnormalities. This review summarizes current evidence indicating that multiple antioxidants, including melatonin, vitamin C, resveratrol, and epigallocatechin gallate, alleviate EDC-induced reproductive toxicity by targeting epigenetic dysregulation. Their protective effects encompass scavenging excessive reactive oxygen species, activating endogenous antioxidant signaling cascades, restoring activity of epigenetic enzymes, and rectifying aberrant histone modification profiles, contributing to the maintenance of epigenetic homeostasis in germ cells. This review clarifies the intrinsic mechanistic link among EDC exposure, oxidative stress, epigenetic dysregulation and reproductive toxicity, which provides a theoretical basis for formulating reproductive health protection strategies against EDC exposure and guides the exploration of clinical epigenetic biomarkers. Full article

Vascular smooth muscle cell (VSMC) control of phenotypic states through regulation of contractile gene expression is critical for vascular homeostasis and for participation in pathological vascular remodeling, such as atherosclerosis. Cohorts of molecular and cellular processes, including transcriptional and post-transcriptional repression of VSMC contractile genes, context-dependent activation of pathological gene sets, proliferation, and migration, coordinately contribute to SMC phenotypic plasticity. Epigenetic (histone post-translational modifications, DNA methylation) and epitranscriptomic (RNA modifications) mechanisms have been implicated in the activation or repression of the VSMC gene repertoire. Among them, methylation exhibits complex, multifaceted, and, in some instances, opposing roles in regulating gene activation. Methylation-mediated epigenetic programming complexity stems from the multiplicity of methylation substrates and enzymes regulating methylation and demethylation. The role and relevance of methylation in regulating VSMC phenotype are often restricted to a given methylation substrate, methylation enzymes, or subsets of genes. The goal of this review is to integrate in vitro and in vivo studies that uncover methylation-mediated VSMC regulation, to assess the overall contribution of methylation-regulating enzymes. We will explore how atherosclerosis-relevant upstream regulatory mechanisms and rate-limiting cofactors of methylation enzymes, including inflammation, metabolism, and hypoxia, affect methylation enzyme activity. Lastly, we will discuss emerging evidence for non-canonical mechanisms by which methylation enzymes may regulate gene expression and their potential role in regulating VSMC phenotype and function. Full article

Kelch-like ECH-associated protein 1 (Keap1) acts as a repressor of nuclear factor-erythroid 2-related factor 2 (Nrf2), a major transcription factor regulating cellular antioxidant response. Keap1 is the substrate adaptor subunit of the cullin 3-RING E3 ubiquitin ligase complex that specifically facilitates Nrf2 ubiquitination and its proteasomal degradation. Keap1 is rich in cysteine residues, and several of them undergo various modifications, such as sulphydration, nitrosylation and glutathionylation under cellular stress conditions. Some of these modifications alter the conformation of Keap1, preventing Nrf2 from ubiquitination and subsequent proteasome-mediated degradation. As a result, newly synthesised Nrf2 translocates to the nucleus to induce the expression of diverse genes involved in protecting cells against oxidative stress. Protein CoAlation is a reversible redox-dependent post-translational modification (PTM) in which coenzyme A (CoA) forms disulphide bonds with oxidised cysteine residues under oxidative or metabolic stress. In this study, we demonstrate for the first time that disulphide Keap1 dimer undergoes CoAlation in cellular response to oxidative stress induced by various oxidising compounds. Furthermore, glucose deprivation also induces CoAlation of the disulphide Keap1 dimer in HEK293/Pank1β cells. We also demonstrate that the Keap1^{11 Cys-less} mutant is not CoAlated in response to diamide treatment or glucose deprivation. In summary, this study uncovers a novel PTM of Keap1 by the key metabolic integrator CoA, which provides new insights into the regulation of the Keap1-Nrf2 antioxidant pathway under oxidative and metabolic stress. Full article

Sulfane sulfur species are increasingly recognized as integral cellular components involved in signaling pathways and cytoprotection against oxidative stress in mammals. While their production in bacteria has been extensively studied, their functional role in bacterial oxidative stress defense remains poorly understood. Here, we demonstrate that sulfane sulfur generated by sulfide: quinone oxidoreductase decreases H₂O₂ sensitivity in Pseudomonas aeruginosa PAO1. Notably, this protective mechanism does not depend on sulfane sulfur acting as a direct H₂O₂ scavenger via nucleophilic reactions. Through persulfidation proteomic profiling, we reveal that persulfidation is a prominent post-translational modification in P. aeruginosa, reflecting the prevalence of deprotonated sulfane sulfur species. These species modify cysteine residues in proteins, including the well-known oxidative stress regulator OxyR. Specifically, sulfane sulfur modifies OxyR at Cys199 to form persulfidated OxyR C199-SSH, contributing to a single-Cys activated state that modulates promoter activity and DNA-binding affinity. Furthermore, sulfane sulfur-mediated persulfidation protects the critical cysteine residue of LpdG, a ROS-vulnerable dihydrolipoamide dehydrogenase, from irreversible overoxidation. Although LpdG is not part of the canonical H₂O₂-scavenging system, its preservation is essential for cell viability under oxidative stress. These findings establish endogenous sulfane sulfur species as key mediators of antioxidant defense in P. aeruginosa. Full article

Myocardial fibrosis is a common pathological feature of multiple cardiovascular diseases, including heart failure, hypertension, and myocardial infarction, and is associated with poor prognosis. Despite extensive research, clinically validated molecular biomarkers for early diagnosis and reliable therapeutic targets for myocardial fibrosis remain limited. Post-translational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, SUMOylation, and glycosylation, are critical regulators of fibrosis-related signaling pathways, yet a systematic bioinformatics-driven identification of PTM-related hub genes has not been performed. Three publicly available GEO datasets (GSE57345, GSE133054, GSE76314) comprising cardiac tissue from heart failure and control patients were integrated. Differentially expressed genes (DEGs) were identified using the limma package, then intersected with a curated PTM gene set derived from PhosphoSitePlus and UniProt databases. Weighted gene co-expression network analysis (WGCNA) identified fibrosis-associated modules, and protein–protein interaction (PPI) network analysis via STRING and CytoHubba pinpointed hub genes. Diagnostic performance was assessed by receiver operating characteristic (ROC) analysis across independent validation cohorts. Immune cell infiltration was estimated using CIBERSORT.Molecular docking with AutoDock Vina (version 1.2.3) was performed to evaluate binding affinity of FDA-approved cardiovascular drugs against identified hub protein targets. A total of 863 DEGs were identified in the training cohort (|log₂FC| > 1.0, adjusted p < 0.05), of which 138 overlapped with the PTM gene set. WGCNA revealed a turquoise module (r = 0.79, p < 0.001) most significantly correlated with fibrosis severity. PPI analysis identified five hub genes: SIRT3, SMAD3, NEDD4L, UBC9, and CAMK2D. ROC analysis demonstrated strong diagnostic performance (AUC range: 0.82–0.92) validated in independent cohorts. Hub genes showed significant correlations with M2 macrophage infiltration. Molecular docking identified spironolactone and finerenone as top-ranked ligands with binding energies of −8.7 and −8.4 kcal/mol against SMAD3 and SIRT3, respectively. This study, which is entirely in silico and based on publicly available transcriptomic datasets, systematically identifies five PTM-related hub genes as candidate diagnostic biomarkers and prioritised drug-repurposing targets in myocardial fibrosis. These findings are hypothesis-generating and require experimental validation (protein-level confirmation, cell- and animal-based functional assays, and biophysical binding studies) before any diagnostic or therapeutic claim can be made. Full article

Lysine lactylation (Kla), a novel post-translational modification (PTM) discovered in 2019, establishes a critical link between cellular metabolism and epigenetic regulation. A growing number of studies have reported that it is involved in several physiological and pathological processes. Traditional experimental methods for identifying Kla sites are time-consuming and labor-intensive; in contrast, computational prediction models offer efficient and systematic alternatives for high-throughput screening of potential modification sites. In this review, we summarize computational methods and data resources used for Kla site prediction. The biological roles of Kla in major human diseases, such as cancers, cardiovascular diseases, and neurological diseases, were summarized. Furthermore, a summary and comprehensive overview of seven Kla site prediction models is presented, covering dataset construction, methodological principles, and evaluation methods. Finally, the challenges and future trends in Kla prediction have been discussed. Full article