A Metabo‐Reprogramming Niche Remodeling System Halts Osteoarthritis by Restoring the FGF21‐Arginine Axis

ABSTRACT

Osteoarthritis (OA), a global leading cause of chronic pain and disability, lacks disease‐modifying osteoarthritis drugs (DMOADs) targeting its core pathogenesis. scRNA‐seq of human OA cartilage showed marked depletion of a high‐arginine‐metabolism chondrocyte subpopulation driving cartilage degeneration, with its key upstream regulator FGF21, significantly downregulated in OA cartilage. Mechanistically, FGF21 rescues IL‐1β‐induced chondrocyte dysfunction via ASS1/ASL ‐mediated arginine biosynthesis, an effect abrogated by ASS1 knockdown, confirming the FGF21‐arginine pathway's role and FGF21 as a therapeutic target. Guided by this mechanism, we engineered a hydrogel‐based bioinspired metabo‐reprogramming niche remodeling system (MetaRemod) to achieve precise and efficient delivery of FGF21 to OA chondrocytes. In a mouse OA model, MetaRemod effectively halted OA progression by sustaining targeted delivery of bioactive FGF21, restoring chondrocyte arginine metabolism, preserving cartilage structure and joint space, restoring subchondral bone integrity, and mitigating synovitis. Critically, scRNA‐seq of treated cartilage confirmed the restoration of the depleted “high‐arginine‐metabolism” chondrocyte subpopulation, directly validating that MetaRemod reverses OA's core metabolic defect. This study establishes the FGF21‐arginine metabolic axis as a key therapeutic target for OA and validates MetaRemod as a promising strategy that synergizes targeted FGF21 delivery and metabolic reprogramming, laying a solid foundation for the clinical translation of metabolic reprogramming‐based DMOADs.