Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9
Introduction: 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...
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1559744/full |
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| author | Yufang Dai Shunshun Wang Shunshun Wang Jiayi Luo Huiming Yu Huiming Yu Qianqian Du Qianqian Du Shuwan Hou Minfu Liu Shan Jiang Shan Jiang Huajiao Xu Huajiao Xu Siyi Ye Siyi Ye Muhammad Farrukh Nisar Haiyan Chen Jiaqin Wu Jiaqin Wu |
| author_facet | Yufang Dai Shunshun Wang Shunshun Wang Jiayi Luo Huiming Yu Huiming Yu Qianqian Du Qianqian Du Shuwan Hou Minfu Liu Shan Jiang Shan Jiang Huajiao Xu Huajiao Xu Siyi Ye Siyi Ye Muhammad Farrukh Nisar Haiyan Chen Jiaqin Wu Jiaqin Wu |
| author_sort | Yufang Dai |
| collection | DOAJ |
| description | Introduction: 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.Methods: The therapeutic effect of GAS on RA was verified by constructing RA models in vivo and in vitro. Molecular docking, surface plasmon resonance (SPR) assays, overexpression and silencing experiments were used to verify the results.Results:In vitro 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 (KD) of 413.72 μM. Overexpression and silencing experiments revealed that GAS destabilized KAT8, thereby reducing H3K9la levels. In vivo, 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.Discussion: 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. |
| format | Article |
| id | doaj-art-ce1e5cbccec14127ab068475f4aa6d96 |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-ce1e5cbccec14127ab068475f4aa6d962025-08-20T02:49:44ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-03-011610.3389/fphar.2025.15597441559744Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9Yufang Dai0Shunshun Wang1Shunshun Wang2Jiayi Luo3Huiming Yu4Huiming Yu5Qianqian Du6Qianqian Du7Shuwan Hou8Minfu Liu9Shan Jiang10Shan Jiang11Huajiao Xu12Huajiao Xu13Siyi Ye14Siyi Ye15Muhammad Farrukh Nisar16Haiyan Chen17Jiaqin Wu18Jiaqin Wu19Minda Hospital of Hubei Minzu University, Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Disease, Enshi, ChinaHubei Shizhen Laboratory, Wuhan, ChinaSchool of Pharmacy, Hubei University of Chinese Medicine, Wuhan, ChinaCollege of Sports and Health, Hubei University of Chinese Medicine, Wuhan, ChinaHubei Shizhen Laboratory, Wuhan, ChinaSchool of Pharmacy, Hubei University of Chinese Medicine, Wuhan, ChinaHubei Shizhen Laboratory, Wuhan, ChinaSchool of Pharmacy, Hubei University of Chinese Medicine, Wuhan, ChinaSchool of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, ChinaSchool of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, ChinaHubei Shizhen Laboratory, Wuhan, ChinaSchool of Pharmacy, Hubei University of Chinese Medicine, Wuhan, ChinaHubei Shizhen Laboratory, Wuhan, ChinaSchool of Pharmacy, Hubei University of Chinese Medicine, Wuhan, ChinaHubei Shizhen Laboratory, Wuhan, ChinaSchool of Pharmacy, Hubei University of Chinese Medicine, Wuhan, ChinaDepartment of Physiology and Biochemistry, Cholistan University of Veterinary and Animal Sciences (CUVAS), Bahawalpur, PakistanRespiratory Medicine, Wuhan University of Science and Technology Affiliated Geriatric Hospital, Wuhan, ChinaSchool of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, ChinaNational Innovation and Attracting Talents “111” base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, ChinaIntroduction: 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.Methods: The therapeutic effect of GAS on RA was verified by constructing RA models in vivo and in vitro. Molecular docking, surface plasmon resonance (SPR) assays, overexpression and silencing experiments were used to verify the results.Results:In vitro 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 (KD) of 413.72 μM. Overexpression and silencing experiments revealed that GAS destabilized KAT8, thereby reducing H3K9la levels. In vivo, 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.Discussion: 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.https://www.frontiersin.org/articles/10.3389/fphar.2025.1559744/fullrheumatoid arthritisgastrodinhistone lactylationKAT8H3K9glycolysis |
| spellingShingle | Yufang Dai Shunshun Wang Shunshun Wang Jiayi Luo Huiming Yu Huiming Yu Qianqian Du Qianqian Du Shuwan Hou Minfu Liu Shan Jiang Shan Jiang Huajiao Xu Huajiao Xu Siyi Ye Siyi Ye Muhammad Farrukh Nisar Haiyan Chen Jiaqin Wu Jiaqin Wu Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9 Frontiers in Pharmacology rheumatoid arthritis gastrodin histone lactylation KAT8 H3K9 glycolysis |
| title | Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9 |
| title_full | Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9 |
| title_fullStr | Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9 |
| title_full_unstemmed | Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9 |
| title_short | Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9 |
| title_sort | gastrodin attenuates rheumatoid arthritis by targeting kat8 to inhibit the lactylation of h3k9 |
| topic | rheumatoid arthritis gastrodin histone lactylation KAT8 H3K9 glycolysis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1559744/full |
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