Zhu Xiaoying, Lu Hanya, Li Wenjing, Niu Sijia, Xue Jiawei, Sun Haoyuan, Zhang Juan, Zhang Zhiyi
Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Department of Orthopedics, Heilongjiang Provincial Hospital, Harbin 150001, China.
Gene. 2025 Feb 5;936:149106. doi: 10.1016/j.gene.2024.149106. Epub 2024 Nov 17.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint destruction, with emerging evidence implicating gut microbiota dysbiosis in its pathogenesis. The current study explores the role of ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, in modulating gut microbiota and metabolic dysregulation through the enzyme peptidyl arginine deiminase 4 (PAD4) in collagen-induced arthritis (CIA) mouse model. Our findings demonstrate that ferroptosis exacerbates RA-related inflammatory responses and joint damage by upregulating PAD4 expression, which, in turn, influences the gut microbial composition and associated metabolite profiles. Erastin, a known ferroptosis agonist, significantly increased the relative abundance of pro-inflammatory bacteria such as Proteobacteria while reducing beneficial taxa like Firmicutes and Bacteroidetes. This microbial shift was associated with heightened oxidative stress and an imbalance in key metabolites, such as lysophosphatidyl ethanolamine 14:0 (LysoPE 14:0), further exacerbated by ferroptosis. Co-treatment with GSK484, a PAD4 inhibitor, reversed these effects, restoring microbial homeostasis and reducing joint inflammation. This study suggests that ferroptosis-mediated PAD4 activity contributes to RA pathogenesis by disrupting the gut-joint axis, providing novel insights into potential therapeutic targets for RA. Our results highlight the intricate interplay between immune-mediated cell death, gut microbiota, and systemic inflammation, emphasizing the importance of ferroptosis as a therapeutic target in mitigating RA progression.
类风湿性关节炎（RA）是一种全身性自身免疫性疾病，其特征为慢性炎症和关节破坏，越来越多的证据表明肠道微生物群失调参与其发病机制。本研究通过胶原诱导性关节炎（CIA）小鼠模型，探讨铁死亡（一种由铁依赖性脂质过氧化驱动的程序性细胞死亡形式）在通过肽基精氨酸脱亚氨酶4（PAD4）调节肠道微生物群和代谢失调中的作用。我们的研究结果表明，铁死亡通过上调PAD4表达加剧了类风湿性关节炎相关的炎症反应和关节损伤，而PAD4表达反过来又影响肠道微生物组成和相关代谢物谱。已知的铁死亡激动剂埃拉司亭显著增加了变形菌等促炎细菌的相对丰度，同时减少了厚壁菌门和拟杆菌门等有益菌群。这种微生物变化与氧化应激增加和关键代谢物失衡有关，如溶血磷脂酰乙醇胺14:0（LysoPE 14:0），铁死亡进一步加剧了这种失衡。用PAD4抑制剂GSK484联合治疗可逆转这些作用，恢复微生物稳态并减轻关节炎症。本研究表明，铁死亡介导的PAD4活性通过破坏肠-关节轴促进类风湿性关节炎的发病机制，为类风湿性关节炎潜在治疗靶点提供了新的见解。我们的结果强调了免疫介导的细胞死亡、肠道微生物群和全身炎症之间的复杂相互作用，强调了铁死亡作为减轻类风湿性关节炎进展的治疗靶点的重要性。
