circ-CBFB调控p66Shc/OMA1信号轴影响线粒体动力学在对乙酰氨基酚肝损伤中的作用及机制研究

线粒体动力学障碍是对乙酰氨基酚（APAP）肝损伤的关键机制。我们研究首次发现：APAP肝损伤中p66Shc表达显著增加，敲减p66Shc明显改善APAP肝损伤线粒体动力学。进一步发现：抑制线粒体内膜蛋白酶OMA1泛素化是p66Shc引起APAP肝损伤线粒体动力学障碍的重要途径；生物信息学预测和预实验提示circ-CBFB可通过海绵效应调控p66Shc的表达。据此提出科学假说：p66Shc抑制OMA1泛素化调节线粒体动力学在APAP肝损伤中发挥重要作用，通过circ-CBFB的海绵效应调控p66Shc/OMA1信号轴减轻APAP肝损伤。本研究利用基因模式动物及分子生物学技术，探讨circ-CBFB调控p66Shc/OMA1信号轴影响线粒体动力学在APAP肝损伤中的作用及机制，为APAP肝损伤治疗提供新的策略及药物研发靶标。

Mitochondrial dynamics imbalance is the key mechanism of acetaminophen (APAP)-induced liver injury. Our preliminary studies found that in APAP-induced liver injury p66Shc expression is significantly increased, and knock-down of p66Shc obviously alleviates mitochondrial dynamics imbalance of APAP-induced liver injury. We further found that inhibition of mitochondrial inner membrane protease (OMA1) ubiquitination is an important pathway of mitochondrial dynamics imbalance induced by p66Shc in APAP-induced liver injury. Bioinformatics and pre-experiment indicated that circ-CBFB can regulate p66Shc expression through sponge effect. Therefore, we hypothesize that p66Shc, which regulates mitochondrial dynamics by inhibiting OMA1 ubiquitination, plays a vital role in APAP-induced liver injury. Modulation of p66Shc/OMA1 axis by circ-CBFB through sponge effect can alleviate mitochondrial dynamics imbalance in APAP-induced liver injury. In this study, by utilizing genetic animal model and molecular biological techniques, we investigate the role and mechanism of circ-CBFB-p66Shc/OMA1 signaling in APAP-induced liver injury and intend to provide a novel therapeutic strategy and a pharmacological target for the treatment of APAP-induced liver injury.