Berberine inhibits protein citrullination of fibroblast-like synoviocytes by suppressing autophagy via STAT3/PAD4 pathway

作者：Yining Song, Fan Zhang, Yun He, Yuhui Li, Fupin Hu, Yuan Gao, Shi-ye Zong, Ying Wang, Xiao-yu Gao, Qian Tang, Xin-meng Jiang, Fan Tong, Liping Yan, Fang Wei · 发表于：Phytomedicine · 年份：2025 · DOI：10.1016/j.phymed.2025.157706 · 被引用次数：3 · 研究领域：Berberine and alkaloids research、Autophagy in Disease and Therapy、Ginseng Biological Effects and Applications

BACKGROUND: Nearly 50% of patients with rheumatoid arthritis (RA) fail to respond adequately to current therapies within a clinically effective timeframe. Previous studies have demonstrated that berberine (BBR) exerts therapeutic effects in RA, however, neither its targets nor associated mechanisms have been investigated. PURPOSE: To identify the direct BBR target and elucidate its molecular mechanism in RA. METHODS: The BBR effects on autophagy and protein citrullination were evaluated using MH7A cells and rats with adjuvant-induced arthritis (AA). Network pharmacology was employed to predict potential BBR target genes in RA. Molecular docking, cellular thermal shift assay (CETSA), solvent-induced protein precipitation (SIP), and surface plasmon resonance (SPR) were conducted to confirm target binding. Western blotting, transmission electron microscopy, immunofluorescence co-localization, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, and qRT-PCR were performed to investigate the molecular pathways involved. RESULTS: BBR reduced citrullinated protein levels by suppressing autophagy in MH7A cells. Network pharmacology suggested STAT3 as a potential BBR target. Molecular docking, CETSA, SIP, and SPR confirmed binding between BBR and STAT3. In AA rats, BBR treatment significantly lowered serum ACPA levels and decreased the levels of cVIM, citH3, p-STAT3, PAD4, and autophagy markers in AA-FLSs. Mechanistic studies show that STAT3 might directly binds to t...