Mitochondrial dysfunction plays a central role in nonalcoholic fatty liver disease (NASH). Zhao et al. report that the mitochondrial circular RNA steatohepatitis-associated circRNA ATP5B regulator (SCAR) account for a considerable fraction of downregulated circRNAs in NASH fibroblasts liver fibroblasts from patients with NASH.
Overexpression of SCAR in NASH fibroblasts blocks mitochondrial permeability transition pore opening, inhibiting mitochondrial reactive oxygen species output and subsequent fibroblast activation.
In high-fat diet-fed mice, delivery of SCAR to liver fibroblasts using mitochondria-targeting nanoparticles mitigated insulin resistance and cirrhosis. in patients with NASH, downregulation of SCAR correlated with steatosis-to-NASH progression.
The authors identify a mitochondrial circRNA that drives metaflammation and could serve as a therapeutic target for NASH.