Aucubin alleviates osteoarthritis by inhibiting chondrocyte ferroptosis via regulation of the Keap1/NRF2 pathway

Osteoarthritis (OA) is a degenerative joint disorder characterized by chondrocyte dysfunction and progressive cartilage destruction, with ferroptosis emerging as a key contributor to disease pathogenesis. This study investigates the therapeutic potential of Aucubin, a natural iridoid glycoside, in OA treatment through modulation of the Keap1/NRF2 pathway and ferroptosis inhibition. Using an in vitro OA model established by IL-1β treatment of immortalized human chondrocytes (HCs), we demonstrate that Aucubin significantly improves cell viability, colony formation capacity, and migratory potential while promoting cell cycle progression. Aucubin also reduces ferroptosis-associated oxidative damage by decreasing MDA, GSSG, Fe2+, and ROS levels while increasing GSH content. Fer-1 ferroptosis inhibitor further supports this result. Molecularly, qPCR and Western blot analyses reveal that Aucubin upregulates NRF2 expression while suppressing Keap1 and modulating the levels of ferroptotic markers. These findings are further corroborated in a surgically induced OA rat model, where Aucubin administration attenuates cartilage degradation, restores Keap1/NRF2 expression, and normalizes ferroptosis-related protein expression. Our preliminary findings suggest that aucubin exerts its chondroprotective effects by inhibiting ferroptosis, at least partially through activation of the Keap1/NRF2 pathway, and may represent a potential therapeutic agent for osteoarthritis.