Targeting the gut-joint axis: Ferrostatin-1 alleviates Collagen-Induced arthritis and is associated with alterations in microbiota-derived metabolites.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and progressive bone destruction. While ferroptosis has recently been implicated in RA pathogenesis, the mechanisms linking ferroptosis inhibition to the gut-joint axis remain poorly understood. This study investigated the therapeutic efficacy of the specific ferroptosis inhibitor Ferrostatin-1 (Fer-1) in a collagen-induced arthritis (CIA) mouse model, specifically examining its regulatory effects on gut microbiota and metabolic profiles. We employed 16S rDNA sequencing and untargeted metabolomics to analyze fecal samples, assessing alterations in microbial community structure and metabolic function following Fer-1 administration. Our results demonstrate that Fer-1 treatment significantly alleviated clinical symptoms, evidenced by reduced arthritis scores and mitigated bone erosion. Microbiome analysis revealed that Fer-1 partially changed CIA-induced specific microbial populations, characterized by an enrichment of beneficial genera such as Bacteroides and a reduction in the phylum Actinobacteriota. Furthermore, metabolomic profiling indicated that Fer-1 changed the levels of critical anti-inflammatory metabolites, specifically short-chain fatty acids (SCFAs), uridine, and indole derivatives. In conclusion, this study suggests that the anti-arthritic effects of Fer-1 may be associated with the remodeling of the partially gut microbiota and an altered profile of protective metabolites, thereby suggesting that the ferroptosis-microbiome axis may serve as a potential therapeutic target in RA management.