MicroRNA-21 is a potential therapeutic agent targeting Tgfbi and mitigating high-fat-diet-induced liver disease and cancer.

Liver disease, including hepatocellular carcinoma (HCC), is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In this study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic-dysfunction-associated steatotic liver disease (MASLD), metabolic-associated steatohepatitis (MASH), and HCC within the context of a Western choline-deficient (CD) high-fat diet (HFD) and offer potential therapeutic insights. We found that reduced miR-21 levels correlated with liver-disease progression in wild-type (WT) mice fed on CD-HFD, while miR-21-knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. miR-21 directly targets Transforming growth factor beta-induced (Tgfbi), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of an miR-21 mimic in WT livers effectively improves insulin sensitivity, steatosis, fibrosis, Tgfbi expression, and tumor burden in CD-HFD conditions. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in HFD environments.