Inhibition of JMJD3 attenuates acute liver injury by suppressing inflammation and oxidative stress in LPS/D-Gal-induced mice.

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.