Gamma-oryzanol alleviates osteoarthritis development by targeting Keap1-Nrf2 binding to interfere with chondrocyte ferroptosis

Osteoarthritis (OA) is a prevalent joint disorder pathologically correlated to chondrocyte ferroptosis. Gamma-oryzanol (gamma-Ory), as a first-line drug for autonomic disorders, aroused our interest because of its antioxidant, lipid-lowering, and hypoglycemic potential. The purpose of this study was to investigate the potential impact and mechanism of gamma-Ory in treating OA. And the inhibition of gamma-Ory in extracellular matrix molecule (ECM) degradation, ferroptosis, and Keap1-Nrf2 binding in IL-1 beta-exposed chondrocytes was detected via immunoblotting, immunofluorescence, and co-immunoprecipitation. Micro-CT, SO staining, and immunofluorescence have been conducted to assess the impact of gamma-Ory treatment on ACLT-mediated OA in rats at both imaging and histological stages. We found that gamma-Ory dose-dependently suppressed IL-1 beta-induced ECM deterioration and chondrocyte ferroptosis. Our animal experiments revealed that gamma-Ory delayed ACLT-mediated OA development. Mechanistically, gamma-Ory interfered with the binding of Keap1 to Nrf2 to promote the latter's nuclear import, thereby increasing the expression of detoxification enzymes. Summarily, our works support gamma-Ory's potential as a candidate drug for the treatment of OA.