PRG4 (proteoglycan 4) is a critical joint lubricant and extracellular matrix component essential for articular cartilage homeostasis. The protein is specifically expressed in the superficial zone of articular cartilage and synovium, where it confers compression resistance to the extracellular matrix 1. PRG4 is produced by distinct populations of synovial fibroblasts, particularly Prg4+ lining fibroblasts that differentiate from Dpp4+ mesenchymal progenitor cells in response to joint injury 23. Mechanistically, PRG4 expression is regulated by FoxO1 transcription factors, which promote autophagy and protect against oxidative stress in chondrocytes 4. Following cartilage injury, iPSC-derived cartilage organoids acquire PRG4 expression through SIK3 inactivation pathways, facilitating joint lubrication and tissue integration 5. PRG4 dysfunction is implicated in osteoarthritis (OA) pathogenesis; deficiency contributes to cartilage degeneration and whole-joint disorder progression 61. Therapeutically, PRG4 induction via HDAC inhibitors like panobinostat suppresses OA-associated inflammatory mediators and matrix-degrading enzymes while improving pain behaviors in murine models 4. PRG4 is also associated with Camptodactyly-arthropathy-coxa vara-pericarditis syndrome, indicating broader developmental significance. Understanding PRG4 regulation represents a promising avenue for developing disease-modifying OA treatments.