MicroRNA-29a attenuates inflammation and fibrosis in an animal model of NASH through MCJ inhibition and hippo pathway regulation.

Non-alcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease, is characterized by steatosis, inflammation, and fibrosis. Mitochondrial dysfunction plays a key role in its development. Methylation-controlled J protein (MCJ), a negative regulator of mitochondrial respiration, promotes oxidative stress and lipid buildup, while its deficiency enhances mitochondrial function. Notably, miR-29a exhibits anti-inflammatory, anti-fibrotic, and mitochondrial-protective effects in liver disease. This study examined the protective role of miR-29a in NASH by exploring its effect on MCJ expression. In vitro and in vivo NASH models were used to assess hepatocyte injury. Overexpression of miR-29a significantly decreased MCJ levels, improved mitochondrial respiration, and reduced hepatic lipid accumulation and oxidative stress. Additionally, miR-29a inhibits the nuclear translocation of Yes-associated protein (YAP), thereby reducing the expression of pro-inflammatory genes and supporting hepatocyte survival and apoptosis. Meanwhile, cyclin-dependent kinase 6 (CDK6), a YAP target, was upregulated by the methionine- and choline-deficient diet in wild-type mice but decreased in miR-29a transgenic mice. The expression of pyroptosis-related markers, including NLR family pyrin domain containing 3, Caspase-1, and Gasdermin D, was significantly lower in miR-29a-treated models, indicating suppression of pyroptotic cell death. In conclusion, miR-29a plays a protective role in NASH by targeting key pathogenic pathways, such as MCJ-mediated mitochondrial dysfunction, YAP/CDK6-driven inflammation, and pyroptosis. These findings highlight miR-29a as a promising therapeutic target for reducing hepatocyte injury and provide new mechanistic insights into NASH progression, supporting its role in decreasing inflammation and fibrosis through MCJ inhibition and Hippo pathway regulation.