Fenofibrate restores cartilage homeostasis and attenuates ferroptosis-associated injury in osteoarthritis

Ferroptosis-associated oxidative injury is increasingly recognized as a contributor to chondrocyte dysfunction and cartilage degeneration during osteoarthritis (OA) progression; however, its relationship with impaired autophagy remains incompletely understood. This study investigated whether fenofibrate protects against OA progression by attenuating oxidative stress- and ferroptosis-associated injury and restoring autophagy-related activity. OA was induced in rats by destabilization of the medial meniscus (DMM). In vitro, chondrocytes were challenged with tert-butyl hydroperoxide (TBHP), an oxidative stress inducer that reproduces several ferroptosis-associated features. Ferroptosis-associated changes, oxidative stress, extracellular matrix homeostasis, and autophagy-related activity were assessed. Autophagy was pharmacologically inhibited to evaluate whether autophagy-related activity contributes to fenofibrate-mediated protection. Therapeutic efficacy was further evaluated in vivo in the DMM model. Enhanced ferroptosis-associated alterations were observed in cartilage tissues from DMM-induced OA rats and in TBHP-challenged chondrocytes. These changes were accompanied by reduced autophagy-related markers. Fenofibrate restored autophagy-related activity, reduced oxidative stress, iron accumulation, and lipid peroxidation, and preserved extracellular matrix homeostasis in vitro. Importantly, autophagy inhibition substantially weakened the anti-ferroptotic and matrix-protective effects of fenofibrate, suggesting that autophagy-related activity contributes to its protective actions. Consistently, fenofibrate alleviated cartilage degeneration and improved OA pathology in vivo. Fenofibrate alleviates OA progression and protects cartilage by reducing oxidative stress- and ferroptosis-associated injury. These protective effects are accompanied by restoration of autophagy-related activity, suggesting that modulation of the autophagy–ferroptosis interplay may contribute to fenofibrate-mediated chondroprotection.