Metabolic dysfunction-associated steatotic liver disease (MASLD) is a health burden that is globally rising in parallel with its etiological factors, which include type 2 diabetes and obesity. This pathological spectrum can lead to complications such as hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC), making it urgent to find novel diagnostic and therapeutic solutions. MicroRNAs (miRNAs) are small RNA molecules that modulate different hepatic processes by binding to and repressing hundreds of target mRNAs. Many miRNAs have been shown to control key aspects of hepatic metabolism, including glucose and lipid anabolism and catabolism. In addition, miRNAs regulate the expression of tumor suppressors and oncogenes, positioning them as critical contributors to hepatocarcinogenesis. Therefore, miRNAs represent promising candidates for the development of novel therapeutic strategies in MASLD and MASLD-associated HCC. Our work has focused on two specific miRNAs – miR-22 and miR-149. We have demonstrated that miR-22 has a protective role in the liver during MASLD, as its genetic ablation exacerbates diet-induced MASLD and obesity in vivo by promoting hepatic lipid synthesis and accumulation. In a subsequent study, we further established miR-22 as a tumor suppressive miRNA, showing that its loss enhances hepatocarcinogenesis under both normal and obesogenic conditions. Additionally, we have shown that miR-149 is upregulated in hepatic steatosis and that its downregulation alleviates disease severity. This work also highlighted human liver organoids as a relevant in vitro model for studying miRNA function. Collectively, these results identify miR-22 and miR-149 as promising therapeutic targets in MASLD and MASLD-associated HCC.