{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T00:08:19Z","timestamp":1792886899421,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The therapeutic effect of GAS on RA was verified by constructing RA models <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Molecular docking, surface plasmon resonance (SPR) assays, overexpression and silencing experiments were used to verify the results.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold><jats:italic>In vitro<\/jats:italic> experiments demonstrated that GAS (10\u201320\u00a0\u03bcM) 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 (<jats:italic>K<\/jats:italic><jats:sub><jats:italic>D<\/jats:italic><\/jats:sub>) of 413.72\u00a0\u03bcM. Overexpression and silencing experiments revealed that GAS destabilized KAT8, thereby reducing H3K9la levels. <jats:italic>In vivo<\/jats:italic>, GAS (20\u00a0mg\/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.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> 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.<\/jats:p>","DOI":"10.3389\/fphar.2025.1559744","type":"journal-article","created":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T23:46:44Z","timestamp":1743119204000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9"],"prefix":"10.3389","volume":"16","author":[{"given":"Yufang","family":"Dai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunshun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiming","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwan","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minfu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajiao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Farrukh","family":"Nisar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1007\/s40265-016-0556-5","article-title":"Biosimilar DMARDs: what does the future hold?","volume":"76","author":"Araujo","year":"2016","journal-title":"Drugs"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5602","DOI":"10.1038\/s41467-024-49930-6","article-title":"KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2","volume":"15","author":"Bi","year":"2024","journal-title":"Nat. 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