MicroRNA-372-3p impairs fatty acid metabolism in hepatocellular carcinoma cells by targeting CPT1A and ACSL4

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with limited effective treatment options. Recent studies highlight the emerging role of microRNAs in HCC biology, including microRNA-372-3p (miR-372-3p), but its precise function in HCC remains controversial. Here, we investigated the role of miR-372-3p in HCC using a transcriptomic approach. Overexpression of miR-372-3p in HCC cell lines significantly impaired proliferation, migration, invasion, and colony formation, indicating a tumor-suppressive function. RNA sequencing and Gene Set Enrichment Analysis (GSEA) revealed downregulation of genes involved in fatty acid metabolism, specifically fatty acid oxidation (FAO). Consistently, miR-372-3p overexpression increased lipid droplet accumulation and triglyceride levels while inhibiting FAO, leading to impaired lipid utilization under glucose deprivation and compromised interactions of lipid droplets with mitochondria and lysosomes. Mechanistically, we identified CPT1A and ACSL4 as direct targets of miR-372-3p using bioinformatics and dual luciferase assays. These findings demonstrate that miR-372-3p acts as a tumor suppressor in HCC by inhibiting FAO and disrupting lipid metabolism, suggesting a potential therapeutic target for HCC treatment.