Qiyi Zhao, et al.

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.