miR-454-3p drives development of hepatic steatosis by negatively regulating JARID2

Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by excessive fat accumulation in the liver. The previous study demonstrated that miR-454-3p was significantly upregulated in metabolic-related diseases type 2 diabetes mellitus (T2DM) and that it regulated high glucose-induced cellular glycolysis. In this study, the regulation of liver lipid metabolism by miR-454-3p in a MASLD model was investigated. Our results showed that the expression of miR-454-3p was significantly increased in the serum of MASLD patients and in HepG2 and HuH-7 cells following free fatty acids (FFA) treatment. Dual luciferase reporter and RNA immunoprecipitation (RIP) assays indicated that miR-454-3p directly interacted with 3' untranslated region (3'-UTR) of Jumonji and AT-rich interaction domain containing 2 (JARID2) mRNA and reduced its expression level. In vitro studies showed that while overexpression of miR-454-3p promoted lipid synthesis in hepatocytes, co-expression of JARID2 reversed this phenotype. Hepatic knockdown of miR-454-3p reduced liver lipid accumulation and thereby ameliorated MASLD in high fat diet (HFD)-fed mice by suppressing lipogenesis. These findings highlight the miR-454-3p/JARID2 axis as a mediator of hepatic lipid accumulation.