NRF2 activation mediates the protective effects of capsaicin against MGO/STZ-induced chondrocyte apoptosis and diabetic articular cartilage injury.

Diabetes mellitus is an independent risk factor for osteoarthritis (OA), and the molecular mechanisms underlying diabetic cartilage damage remain unclear. This study investigated the role of oxidative stress in diabetes-induced chondrocyte injury, especially chondrocyte apoptosis, explored the protective role of the NRF2 antioxidant system, and evaluated the therapeutic potential of capsaicin for diabetic OA. In vivo experiments were conducted on streptozotocin (STZ)-induced diabetic mice, in which cartilage degeneration and subchondral bone remodeling were assessed via Safranin O/Fast Green staining, OARSI scoring and micro-CT, while chondrocyte apoptosis and protein expression were detected by TUNEL staining and immunohistochemistry. In vitro, methylglyoxal (MGO)-treated primary mouse chondrocytes and ATDC5 chondrogenic precursor cells were combined with Nrf2 knockdown/overexpression and N-acetylcysteine (NAC) rescue assays to verify the ROS/NRF2 regulatory mechanism. In vivo, STZ-induced hyperglycemia caused severe cartilage erosion, aberrant subchondral bone remodeling and excessive chondrocyte apoptosis. In vitro, MGO elevated intracellular ROS levels and triggered chondrocyte apoptosis in a concentration-dependent manner, and NAC-mediated ROS scavenging reversed this injury, confirming a ROS-dependent pathogenic mechanism. MGO activated NRF2 signaling time-dependently, and Nrf2 knockdown aggravated whereas Nrf2 overexpression attenuated chondrocyte apoptosis. Importantly, capsaicin activated NRF2 signaling, rescued MGO-induced chondrocyte apoptosis in vitro, and alleviated STZ-elicited articular cartilage degeneration in vivo. In conclusion, diabetes induces ROS-mediated chondrocyte apoptosis and cartilage damage. Capsaicin exerts potent chondroprotective effects against diabetic OA via NRF2 activation, offering a promising therapeutic strategy.