Oxidative stress induces ferroptosis in tendon stem cells by regulating mitophagy through cGAS-STING pathway

Ferroptosis can be considered as a pathogenic cause of tendinopathy and cGAS-STING axis may serve as a novel strategy to prevent tendinopathy as well as other oxidative stress disease. [Display omitted] •Ferroptosis is involved in the progress of tendinopathy induced by fluoroquinolone antibiotics.•Ferroptosis aggravates the tendinopathy by inhibiting tendon lineage differentiation of tendon stem cells.•cGAS-STING axis facilitate ferroptosis through excessive mitophagy in tendon stem cells. Tendinopathy is one of the most prevalent sports injury diseases in orthopedics. However, there is no effective treatment or medicine. Recently, the discovery of tendon stem cells (TSCs) provides a new perspective to find new therapeutic methods for Tendinopathy. Studies have shown that oxidative stress will inevitably cause TSCs injury during tendinopathy, but the mechanism has not been fully elucidated. Here, we report the oxidative damage of TSCs induced by H2O2 via ferroptosis, as well, treatment with H2O2 raised the proportion of mitochondria engulfed by autophagosomes in TSCs. The suppression of mitophagy by Mdivi-1 significantly attenuates the H2O2-induced ferroptosis in TSCs. Mechanically, H2O2 actives the cGAS-STING pathway, which can regulate the level of mitophagy. Interfering with cGAS could impair mitophagy and the classical ferroptotic events. In the rat model of tendinopathy, interference of cGAS could relieve tendon injury by inhibiting ferroptosis. Overall, these results provided novel implications to reveal the molecular mechanism of tendinopathy, by which pointed to cGAS as a potential therapeutic target for the treatment of tendinopathy.