• PLOD2 is identified as a key mediator of the enhanced regenerative and chondroprotective properties of MRL mouse-derived mesenchymal stromal/stem cells (MSC).
• Silencing PLOD2 in MRL MSC reduces glycolytic metabolism, impairing their migratory and chondroprotective functions in vitro.
• In vivo, PLOD2 knockdown in MRL MSC significantly diminishes their ability to protect against collagenase-induced osteoarthritis (CiOA), highlighting its therapeutic potential.
• These findings suggest that targeting PLOD2 or its metabolic pathways could enhance MSC-based therapies for osteoarthritis and other degenerative joint diseases.