High-intensity interval training promotes cartilage repair and ameliorates ferroptosis via SIRT1 in osteoarthritis

Osteoarthritis (OA) is a progressive degenerative joint disease characterized by cartilage degradation, inflammation, and pain. High-intensity interval training (HIIT) has emerged as a promising non-pharmacological intervention that may improve joint function by promoting cartilage repair and attenuating inflammation. This study investigated the effects of HIIT on cartilage ferroptosis and the underlying molecular mechanisms, focusing on SIRT1 in a rat model of knee OA. Sprague-Dawley rats were induced with OA via intra-articular monosodium iodoacetate (MIA) and then subjected to a 6-week HIIT program. Outcomes included gait analysis, mechanical and thermal pain thresholds, histological staining, and molecular assays. HIIT significantly improved gait parameters and pain thresholds, indicating functional recovery. Histology showed enhanced cartilage matrix integrity and repair. HIIT modulated ferroptosis-related markers, including GPX4 and ACSL4, and upregulated SIRT1 with activation of NRF2 signaling and improved iron metabolism within cartilage. Pharmacologic inhibition of SIRT1 (EX527) reversed these benefits, underscoring SIRT1's pivotal role in mediating HIIT's therapeutic effects. In vitro, IL-1β-stimulated primary chondrocytes exhibited reduced SIRT1/NRF2/GPX4 and increased TFRC/ACSL4, whereas lentiviral SIRT1 overexpression restored NRF2-GPX4 signaling and decreased TFRC/ACSL4, supporting a chondrocyte-intrinsic SIRT1-NRF2-GPX4 axis in regulating ferroptosis-associated responses. In conclusion, while direct evidence of ferroptosis markers such as lipid peroxidation and mitochondrial changes is lacking, HIIT alleviates ferroptosis-associated cartilage damage and promotes cartilage repair in OA through SIRT1-dependent mechanisms. These findings support HIIT as a potential non-pharmacological strategy for OA management and provide a mechanistic basis for exercise-based interventions aimed at preserving joint function and reducing OA-related disability.