Bu Chenhan, Xie Yueqing, Weng Jiawei, Sun Youpeng, Wu Hanpeng, Chen Yichun, Ye Yingrong, Zhou Ershun, Yang Zhengtao, Wang Jingjing
School of Animal Science and Technology, Foshan University, Foshan, Guangdong, 528231, China.
School of Animal Science and Technology, Foshan University, Foshan, Guangdong, 528231, China.
Chem Biol Interact. 2025 Sep 5;418:111576. doi: 10.1016/j.cbi.2025.111576. Epub 2025 May 31.
Histone methylation/demethylation represents a pivotal epigenetic mechanism governing heritable gene expression and chromatin architecture, with profound implications for the pathogenesis of hepatic disorders. JMJD3 (KDM6B), a Jumonji domain-containing histone demethylase specifically targeting di- and trimethylated lysine 27 on histone H3 (H3K27me2/3), has emerged as a critical regulator of inflammatory diseases. The study primarily investigates the impact and mechanisms of JMJD3 on acute liver injury. Utilizing both in vitro (LPS-stimulated RAW264.7 macrophages) and in vivo (LPS/d-Galactosamine-induced murine model) systems, we demonstrate that JMJD3 expression is dramatically upregulated during acute liver injury. Strikingly, pharmacological inhibition with the selective JMJD3 inhibitor GSK-J1 or siRNA-mediated JMJD3 silencing robustly attenuated pro-inflammatory cytokine production in macrophages and substantially ameliorated hepatic inflammation and tissue damage in mice. Mechanistically, JMJD3 inhibition elevated global H3K27me3 levels, suppressed NF-κB signaling activation and downstream inflammatory cascades. Furthermore, JMJD3 inhibition activated the Nrf2/HO-1 antioxidant pathway, enhancing cellular defenses against oxidative stress by upregulating key antioxidant enzymes. These findings suggest that JMJD3 orchestrates dual pro-inflammatory and pro-oxidative pathways in liver injury, positioning it as a novel therapeutic target. Our work not only advances the molecular understanding of epigenetic regulation in hepatopathology but also identifies GSK-J1 as a promising pharmacological candidate for mitigating acute hepatic damage.
组蛋白甲基化/去甲基化是一种关键的表观遗传机制，调控着可遗传的基因表达和染色质结构，对肝脏疾病的发病机制有着深远影响。JMJD3（KDM6B）是一种含Jumonji结构域的组蛋白去甲基化酶，特异性靶向组蛋白H3上的二甲基化和三甲基化赖氨酸27（H3K27me2/3），已成为炎症性疾病的关键调节因子。本研究主要探讨JMJD3对急性肝损伤的影响及其机制。利用体外（脂多糖刺激的RAW264.7巨噬细胞）和体内（脂多糖/d-半乳糖胺诱导的小鼠模型）系统，我们证明在急性肝损伤期间JMJD3表达显著上调。引人注目的是，用选择性JMJD3抑制剂GSK-J1进行药理抑制或siRNA介导的JMJD3沉默可显著减弱巨噬细胞中促炎细胞因子的产生，并显著改善小鼠的肝脏炎症和组织损伤。机制上，JMJD3抑制可提高整体H3K27me3水平，抑制NF-κB信号激活和下游炎症级联反应。此外，JMJD3抑制激活了Nrf2/HO-1抗氧化途径，通过上调关键抗氧化酶增强细胞对氧化应激的防御能力。这些发现表明，JMJD3在肝损伤中协调了促炎和促氧化双重途径，使其成为一个新的治疗靶点。我们的工作不仅推进了对肝脏病理学中表观遗传调控的分子理解，还确定GSK-J1是减轻急性肝损伤的有前景的药理候选物。
