Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for H3K27 trimethylation, has emerged as a potential therapeutic target in osteoarthritis (OA). However, its contribution to the multicellular mechanisms driving joint degeneration and pain remains poorly understood. Here, we investigated the effects of pharmacological EZH2 inhibition in a pain-relevant murine OA model and explored its cellular and molecular consequences across OA-associated cell populations. OA was induced in mice by intra-articular monosodium iodoacetate (MIA) injection followed by local administration of the EZH2 inhibitor EPZ-6438. Joint pathology and pain-related behaviors were assessed by histological and functional analyses. Mechanistic studies were performed in primary human OA fibroblast-like synoviocytes and bone marrow-derived cells using targeted gene expression analyses, proteomics and ChIP-seq approaches. EZH2 inhibition reduced cartilage damage, synovial inflammation and pain-related behavioral alterations in vivo. In OA synoviocytes, EPZ-6438 decreased the expression of inflammatory, catabolic and pain-associated mediators while promoting autophagy-related responses. Proteomic and ChIP-seq analyses revealed EZH2-dependent regulation of inflammatory pathways, cellular homeostasis and neuronal-associated processes, including axon guidance-related pathways. ChIP-seq further identified inflammation-dependent EZH2 recruitment to promoters of neurodevelopmental regulators, including PAX6, suggesting a potential contribution of EZH2 to neuronal-associated mechanisms in OA. In addition, EZH2 inhibition reduced macrophage inflammatory activation and osteoclast differentiation. Together, these findings identify EZH2 as a candidate epigenetic regulator linking inflammatory, neuroimmune and osteoimmune pathways across the osteoarthritic joint. Targeting EZH2 may represent a therapeutic strategy to simultaneously modulate joint inflammation, remodeling and pain-associated pathways.
Aquaporins (AQPs) represent a class of integral membrane proteins that function as selective water channels, facilitating the transit of water molecules across biological membranes. Under specific conditions, these proteins may also mediate the permeation of small solutes, including glycerol, hydrogen peroxide, urea, carbon dioxide, and ammonia. Investigations into AQPs have unveiled distinctive structural attributes and functional properties. Evidence indicates that AQPs are broadly distributed across diverse tissues and organ systems in humans, contributing to essential physiological processes. An expanding body of literature highlights the involvement of AQPs in disease pathogenesis and progression, particularly in cellular behaviors such as proliferation and motility, pulmonary gas exchange, and the modulation of non-canonical signaling pathways. This review comprehensively outlines the tissue-specific and subcellular distribution profiles, physiological roles, and regulatory mechanisms associated with AQPs. It further characterizes the alterations in AQP functionality under pathological states, delineates their involvement and mechanistic contributions to multisystem disorders, and provides an overview of therapeutic strategies targeting AQPs, along with their translational prospects. In addition, key gaps in current knowledge are identified, and pivotal research directions, such as tissue-specific modulation and the design of targeted inhibitors and activators, are proposed to advance the translational application of AQPs as diagnostic and therapeutic targets.
Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death that is driven by lipid peroxidation. In the past decade, it has emerged as a core pathogenic mechanism in a wide range of human diseases, such as neurodegenerative disorders, cardiovascular disease, cancer, and notably, reproductive dysfunction. This review provides a comprehensive overview of the molecular mechanisms underlying ferroptosis with a specific focus on the System Xc⁻–GSH–GPX4 axis, iron metabolism, lipid peroxidation, and the regulatory roles of key modulators such as Nrf2, ACSL4, and CISD2. This review also explores the physiological roles of ferroptosis in development, tissue homeostasis, and immune regulation, as well as its pathological contributions to obesity, diabetes mellitus, atherosclerosis, neurodegeneration, stroke, cancer, infectious diseases, and reproductive disorders. A substantial part of this review discusses the role of ferroptosis in the pathogenesis of reproductive disorders, such as male reproductive pathologies, including varicocele, testicular ischemia–reperfusion, cryptorchidism, oligospermia, erectile dysfunction, and testicular cancer, and female pathologies like primary ovarian insufficiency, polycystic ovary syndrome, endometriosis, ovarian cancer, and pre-eclampsia. Moreover, the interplay between ferroptosis and immune dysfunction in reproductive tract infections was highlighted. Furthermore, we evaluated current biomarkers, emerging therapeutic strategies, and key translational challenges, highlighting the promise of ferroptosis-modulating agents for novel diagnostic and therapeutic interventions in reproductive medicine and beyond.
Type 1 diabetes mellitus (T1DM) is characterized by the destruction of pancreatic β-cells, in which the dysfunction of regulatory T cells (Tregs) contributes to impaired immune tolerance. However, Treg heterogeneity remains incompletely understood, which limits the effectiveness of current therapies. Here, we have integrated transcriptome, flow cytometry, glycemic correlation, and cross-model validation to characterize the dysregulation of Tregs and effector T cells (Teffs) in a streptozotocin (STZ)-induced T1DM mouse model. Tregs exhibited a proliferative, effector-like, unstable lineage, and metabolic reprogramming features, marked by increased Melk, Prf1, Gzma and Hk2, and decreased expression of Tnfsf15, Irak3 and Zeb2 in T1DM, and alterations in the transcription-factor networks involving Nfatc2, Elk1, and Ahr. Flow cytometry further revealed that the frequency of splenic Tregs was significantly increased, accompanied by broad upregulation of programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), lymphocyte-activation gene 3 (LAG3), and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3). Meanwhile, expression of glycoprotein A repetitions predominant (GARP) and latency-associated peptide (LAP) was decreased, whereas interleukin (IL)- 17 and interferon-γ (IFN-γ) secretion were increased, suggesting a Treg phenotype with high checkpoint expression and inflammatory features. Cross-model analyses identified concordant IL-15-, IL-36 A-, E2F-, and metabolic programs across the C57BL/6, non-obese diabetic (NOD), and human datasets, including shared genes Smad3, Mki67, and Cxcr4. Teffs also displayed a hyperactivated but transcriptionally imbalanced phenotype in T1DM. Collectively, our findings reveal transcriptional and phenotypic alterations in Tregs and Teffs, providing new insights into T-cell dysregulation and potentially informing the development of Treg-based immunotherapies in T1DM.
Sirtuins (SIRT1–SIRT7) are evolutionarily conserved NAD+-dependent deacylases that function as metabolic sensors, coupling cellular metabolic state to epigenetic, transcriptional and post-translational regulatory programs across distinct subcellular compartments. Despite two decades of research, isoform- and disease-specific aspects remain poorly integrated, limiting both conceptual clarity and therapeutic translation. This review synthesizes recent advances in sirtuin biology into a family-wide framework. Rather than functioning as isolated longevity factors, sirtuins operate as a distributed compartmentalized regulatory network in which nuclear SIRT1, SIRT6 and SIRT7, cytosolic SIRT2 and mitochondrial SIRT3, SIRT4 and SIRT5 collectively govern glucose and lipid metabolism, mitochondrial quality control, autophagy, inflammation and immune tolerance. This network operates across metabolic disorders, cardiovascular and neurodegenerative diseases, inflammatory conditions and cancer, where dysregulated sirtuin signalling influences disease development in a disease- and tissue-specific manner. Therapeutic strategies are evaluated, ranging from isoform-selective small-molecule modulators and NAD+-targeted interventions to emerging protein-degradation approaches, with isoform selectivity, off-target effects and the systemic consequences of NAD+ modulation identified as key translational barriers that have contributed to heterogeneous clinical outcomes. Viewing sirtuins as a context-sensitive compartmentalized network, not isolated targets, offers a coherent framework to guide mechanistic interrogation and the design of more precise sirtuin-based therapies, with priority areas including tissue-selective degradation and network-level biomarkers.
