Chlorogenic acid protects against knee osteoarthritis by targeting the Nrf2/HO-1 redox-ferroptosis axis and inflammatory cartilage degeneration.

Knee osteoarthritis (KOA) is characterized by inflammation, extracellular matrix (ECM) degradation, oxidative stress, and chondrocyte loss. Increasing evidence indicates that inflammation-driven redox imbalance and ferroptotic cell death jointly contribute to cartilage degeneration, yet effective pharmacological strategies capable of simultaneously restoring antioxidant defense and suppressing ferroptosis remain limited. This study investigated whether chlorogenic acid (CGA) protects against KOA by regulating Nrf2-associated antioxidant defense and ferroptotic injury. In IL-1β-stimulated ATDC5 chondrocytes, CGA reduced inflammatory mediator expression, restored Aggrecan and Collagen II, and suppressed MMP3 and MMP13. CGA also decreased reactive oxygen species (ROS), lipid peroxidation, mitochondrial dysfunction, and intracellular Fe2+ accumulation while restoring SLC7A11, GPX4, and FTH1 expression. In an RSL3-induced ferroptosis model, both CGA and ferrostatin-1 attenuated Fe2+ accumulation, malondialdehyde (MDA) production, ferroptosis-defense impairment, and loss of glutathione peroxidase (GPx) activity. CGA enhanced nuclear Nrf2 accumulation and downstream HO-1 signaling, whereas Nrf2 silencing substantially attenuated its antioxidant, matrix-preserving, and anti-ferroptotic effects. In the destabilization of the medial meniscus-induced KOA mouse model, CGA alleviated cartilage degeneration, synovial inflammation, ECM disruption, and ferroptosis-associated changes without overt organ toxicity. These findings extend the established anti-inflammatory and antioxidant actions of CGA by providing functional evidence that CGA attenuates ferroptotic damage and that Nrf2 contributes importantly to its chondroprotective effects.