MicroRNA-21 promotes dysregulated lipid metabolism and hepatocellular carcinoma

The prevalence of hepatocellular carcinoma (HCC) is rising in parallel with increasing obesity and metabolic dysfunction-associated steatohepatitis (MASH). MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and attractive targets for HCC therapy. Here, we sought to identify and characterize dysregulated miRNAs in MASH-driven HCC (MASH-HCC). We profiled miRNA expression in liver tissue from patients with MASH or MASH-HCC and in zebrafish HCC driven by activated β-catenin (CTNNB1), one of the most commonly mutated oncogenes in MASH-HCC. We found overlap between dysregulated human and zebrafish miRNAs, including microRNA-21 (miR-21), which was increasingly upregulated from normal liver to MASH to MASH-HCC. We generated transgenic zebrafish that overexpress or sponge miR-21 in hepatocytes. We found that miR-21 overexpression caused larval liver overgrowth and increased HCC, while miR-21 sponge suppressed β-catenin-driven larval liver overgrowth. By performing histological and lipidomics analysis, we found that overexpression of miR-21, like activated β-catenin (ABC), suppressed lipid accumulation in response to a high cholesterol diet and increased accumulation of acylcarnitines. Thus, miR-21, which is similarly upregulated in human and zebrafish HCC, promotes lipid metabolic changes that may help drive hepatocarcinogenesis.