The “gut microbiota-ferroptosis axis”: a hypothesis for osteoarthritis pathogenesis and therapeutic implications

Knee osteoarthritis, a common type of osteoarthritis (OA), is a significant driver of global disability. Current treatments offer mainly transient symptomatic relief but fail to halt disease progression. Thus, it is critical to find out useful disease modification methods for OA. Accumulating evidences indicated that iron-dependent regulated cell death called ferroptosis contributes to OA recently. The concept that gut-joint axis including gut microbes and their metabolites may participate in OA progression by linking with local and systemic inflammation might be able to facilitate cartilage degradation. The present review delineates the complex association between ferroptosis and the gut-joint axis in OA. This review synthesizes cross-disciplinary evidence to propose a novel hypothetical framework: the "gut microbiota-ferroptosis axis" as a driver of OA progression. We speculate that abnormal iron metabolism and gut microbiota dysbiosis can promote each other and play a synergistic role in promoting ferroptosis of chondrocytes. When gut microbiota dysbiosis occurs, it can accelerate the onset process of osteoarthritis by consuming protective metabolites that inhibit ferroptosis such as serotonin (5-HT) and 3-hydroxyanthranilic acid (3-HAA) and increasing the levels of ferroptosis - promoting compounds such as lipopolysaccharide (LPS). Conversely, reactive oxygen species and lipid peroxides released during ferroptosis can systemically disseminate through blood circulation, exacerbating gut dysbiosis and intestinal barrier dysfunction, thereby establishing a potential self-amplifying loop between ferroptosis and gut dysfunction in OA. Therapeutic interventions targeting this axis, such as resveratrol, and quercetin, show promise by simultaneously modulating gut-joint signaling and suppressing ferroptosis, potentially achieving intestinal barrier recovery and chondrocyte rescue. Future investigations should give priority to dissecting the precise molecular crosstalk within the "gut microbiota-ferroptosis axis" and evaluating combined therapeutic strategies in preclinical models and clinical trials to validate their translational potential for OA.