Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1α, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1α by endoplasmic reticulum (ER) stress-induced CHOP. In vivo, targeting circRNA SCAR alleviates high fat diet-induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.

线粒体在免疫代谢疾病中起关键作用，具有自己的基因组。但是，由于缺乏特定的递送系统，位于线粒体的非编码RNA的功能很大程度上未知。通过非酒精性脂肪性肝炎（NASH）患者肝成纤维细胞的环状RNA（circRNA）表达谱分析，我们观察到线粒体circRNA占NASH成纤维细胞下调circRNA的很大一部分。通过构建靶向线粒体的纳米颗粒，我们观察到位于线粒体中的与脂肪性肝炎相关的circRNA ATP5B调节剂（SCAR）抑制线粒体ROS（mROS）输出和成纤维细胞活化。由PGC-1α介导的circRNA SCAR与ATP5B结合，并通过阻断CypD-mPTP相互作用而关闭mPTP。在体内，靶向circRNA SCAR可减轻高脂饮食引起的肝硬化和胰岛素抵抗。在临床上，circRNA SCAR与脂肪变性到NASH的进展有关。总的来说，我们确定了一种线粒体circRNA，可驱动发炎并充当NASH的治疗靶标。