The role of the HB-EGF-regulated EGFR-mitophagy axis in maintaining cartilage homeostasis and osteoarthritis

This study investigates the mechanism by which heparin-binding epidermal growth factor (HB-EGF) maintains cartilage homeostasis in osteoarthritis (OA) through the epidermal growth factor receptor (EGFR)-mitochondrial autophagy(definition) axis. Given the challenges in OA treatment and the critical role of impaired mitochondrial autophagy in disease progression, this research first identified key regulators using transcriptomic data from human OA cartilage and GEO databases. An in vitro OA model was established via IL-1β induction in chondrocytes, through which HB-EGF was found to reverse the IL-1β-induced metabolic imbalance by downregulating catabolic markers (Mmp13, Adamts5) and upregulating anabolic markers (Acan, Col2a1). Further analysis revealed that HB-EGF enhanced mitophagy, as indicated by increased levels of Pink1, Parkin, and Lc3-II alongside decreased P62. These protective effects were attenuated by the mitophagy inhibitor Mdivi-1, confirming the dependence on this pathway. In conclusion, HB-EGF activates EGFR signaling to promote PINK1/ PARKIN-mediated mitophagy, which facilitates the clearance of damaged mitochondria and improves mitochondrial function, thereby restoring chondrocyte metabolic balance and delaying OA progression, suggesting the EGFR-mitophagy axis as a potential therapeutic target for OA.