Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China.
Int Immunopharmacol. 2024 Sep 10;138:112652. doi: 10.1016/j.intimp.2024.112652. Epub 2024 Jul 10.
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 HO via ferroptosis, as well, treatment with HO raised the proportion of mitochondria engulfed by autophagosomes in TSCs. The suppression of mitophagy by Mdivi-1 significantly attenuates the HO-induced ferroptosis in TSCs. Mechanically, HO 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.
腱病是矫形外科中最常见的运动损伤疾病之一。然而，目前尚无有效的治疗方法或药物。最近，肌腱干细胞（TSCs）的发现为寻找腱病的新治疗方法提供了新的视角。研究表明，氧化应激在腱病过程中不可避免地会导致 TSCs 损伤，但机制尚未完全阐明。在这里，我们报告了 HO 通过铁死亡诱导 TSCs 的氧化损伤，并且 HO 处理提高了 TSCs 中被自噬体吞噬的线粒体的比例。Mdivi-1 对线粒体自噬的抑制显著减轻了 HO 诱导的 TSCs 中铁死亡。在机制上，HO 激活了 cGAS-STING 途径，该途径可以调节线粒体自噬的水平。干扰 cGAS 会损害线粒体自噬和经典的铁死亡事件。在腱病大鼠模型中，干扰 cGAS 可以通过抑制铁死亡来缓解肌腱损伤。总的来说，这些结果为揭示腱病的分子机制提供了新的启示，表明 cGAS 可能是治疗腱病的潜在治疗靶点。
