Ferroptosis Induces gut microbiota and metabolic dysbiosis in Collagen-Induced arthritis mice via PAD4 enzyme
Xiaoying Zhu, Huimin Lü, Wenjing Li, Sijia Niu, Jiawei Xue, Haoyuan Sun, Juan Zhang, Zhiyi Zhang
Abstract
• Ferroptosis exacerbates gut microbiota dysbiosis in CIA mice. • PAD4 upregulation mediates the pro-inflammatory effects of ferroptosis in RA. • Erastin treatment increases pro-inflammatory bacteria and reduces beneficial taxa. • GSK484 reverses erastin-induced microbial and metabolic disruptions in CIA mice. • The study reveals the gut-joint axis as a potential therapeutic target in RA. 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.