Dihydrolipoic acid suppresses ferroptosis in chondrocytes to ameliorate the progression of osteoarthritis by modulating the FOXO1/TXNIP signaling pathway

Osteoarthritis (OA), a common degenerative joint disorder, currently lacks effective therapeutic strategies to alleviate its progression. This study aims to investigate the function and underlying mechanisms of dihydrolipoic acid (DHLA) in inhibiting ferroptosis in chondrocytes and alleviating OA progression. Mouse primary chondrocytes were exposed to IL-1β to induce ferroptosis and treated with DHLA in vitro, followed by the assessment of ferroptosis-related markers and indicators of chondrocyte anabolism and catabolism. The underlying therapeutic mechanisms of DHLA in OA were further investigated through computer network analysis and experimental validation. The surgery destabilization of the medial meniscus was then conducted to establish the mouse OA model before treatment with DHLA. The therapeutic effect of DHLA in OA mice was evaluated through micro-CT and histological analyses. DHLA suppressed the IL-1β-induced increases in levels of intracellular reactive oxygen species, Fe 2+ , lipid peroxidation, and malondialdehyde in chondrocytes, while attenuating the depletion of glutathione, as well as the levels of GPX4 and SLC7A11. Furthermore, the IL-1β-induced reductions in proteoglycans secretion and the levels of Collagen II, Aggrecan, and SOX9 were attenuated by DHLA, while inhibiting the upregulation of MMP13, MMP3, and ADAMTS5. Further studies revealed that the downregulation of FOXO1 expression and the upregulation of TXNIP expression induced by IL-1β were ameliorated by DHLA. The protective effects of DHLA were abolished by AS1842856, a specific FOXO1 inhibitor, whereas this inhibition was reversed by SRI-37330, a specific TXNIP inhibitor. In vivo, DHLA attenuated osteophyte formation and cartilage degeneration induced by DMM surgery in OA model mice. Moreover, the upregulation of MMP13 and TXNIP was suppressed by DHLA, as well as the downregulation of Collagen II, GPX4, and FOXO1 in articular cartilage. DHLA inhibits chondrocytes ferroptosis to alleviate OA progression through the FOXO1/TXNIP signaling pathway, offering a potential treatment strategy for OA. • This study represents the first experimental evidence demonstrating that DHLA inhibits ferroptosis in chondrocytes. • This study provides the first direct demonstration that DHLA suppresses extracellular matrix degradation. • This study unveils, for the first time, the involvement of the FOXO1/TXNIP signaling pathway in the pathogenesis of OA. • This study is the first to demonstrate that DHLA attenuates osteophyte formation and cartilage degeneration in the DMM-induced OA model mice.