Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9

<b>Introduction:</b> Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction, with limited therapeutic options. This study investigated the therapeutic potential of gastrodin (GAS), a natural phenolic glycoside derived from Gastrodia elata, in targeting lysine acetyltransferase 8 (KAT8) to suppress histone H3K9 lactylation (H3K9la), a novel post-translational modification linked to inflammatory responses. <b>Methods:</b> The therapeutic effect of GAS on RA was verified by constructing RA models <i>in vivo</i> and <i>in vitro</i>. Molecular docking, surface plasmon resonance (SPR) assays, overexpression and silencing experiments were used to verify the results. <b>Results:</b> <i>In vitro</i> experiments demonstrated that GAS (10-20 μM) significantly inhibited lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines (IL-6, MMP1, MMP13) in fibroblast-like synoviocytes (FLS) and THP-1 macrophages by downregulating glycolysis and lactate production. Molecular docking and surface plasmon resonance (SPR) assays confirmed KAT8 as a direct target of GAS, with a dissociation constant (<i>K</i> _<i>D</i> ) of 413.72 μM. Overexpression and silencing experiments revealed that GAS destabilized KAT8, thereby reducing H3K9la levels. <i>In vivo</i>, GAS (20 mg/kg) ameliorated joint swelling and synovial hyperplasia in a Sprague-Dawley rat adjuvant-induced arthritis (AIA) model, correlating with decreased H3K9la and IL-6 expression. <b>Discussion:</b> These findings establish GAS as a promising therapeutic agent for RA by modulating KAT8-mediated histone lactylation, providing new insights into epigenetic regulation of inflammation.