Abstract
BACKGROUNDS AND AIMS: The prevalence of hepatocellular carcinoma (HCC) is rising in parallel with increasing obesity and metabolic dysfunction-associated steatohepatitis (MASH). MicroRNAs are key post-transcriptional regulators of gene expression and are attractive targets for HCC therapy. Here we sought to identify and characterize dysregulated microRNAs in MASH-driven HCC (MASH-HCC). APPROACH AND RESULTS: We profiled microRNA expression in liver tissue from patients with MASH and/or MASH-HCC and in zebrafish HCC driven by activated β-catenin (ABC), one of the most commonly mutated oncogenes in MASH-HCC. We found significant overlap between dysregulated human and zebrafish miRNAs, including miR-21, which was increasingly upregulated from normal liver to MASH to MASH-HCC. We generated transgenic zebrafish that overexpress or sponge (downregulate) miR-21. 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 histologic and lipidomic analysis, we found that overexpression of miR-21, like ABC, suppressed lipid accumulation in response to a high cholesterol diet and increased accumulation of acylcarnitines. CONCLUSIONS: Here we characterize microRNA dysregulation in MASH and MASH-HCC in patients, identify miR-21 as increasingly dysregulated from MASH to MASH-HCC, and delineate the impacts of miR-21 overexpression on lipid metabolism and hepatocarcinogenesis in zebrafish β-catenin-driven HCC. This study shows that miR-21, which is similarly dysregulated in human and zebrafish HCC, promotes lipid metabolic changes that may help drive hepatocarcinogenesis.