Acyl-CoA Synthetase Medium-Chain Family Member 5–Mediated Fatty Acid Metabolism Dysregulation Promotes the Progression of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with high incidence and mortality worldwide. Despite diagnostic and therapeutic advancements, HCC remains poorly responsive to treatment, with a poor prognosis. Understanding the molecular mechanisms driving HCC is crucial for developing effective therapies. Emerging evidence indicates that dysregulated fatty acid metabolism contributes to HCC. Acyl-CoA medium-chain synthetase 5 (ACSM5), involved in fatty acid metabolism, is down-regulated in HCC; however, its role is not well understood. This study was used to analyze ACSM5 expression in HCC patient samples and cell lines. The newly established ACSM5-overexpressing HCC cell lines, Huh7-ACSM5 and Hepa1-6–ACSM5, were used to investigate the effects and regulatory mechanisms of ACSM5. The results showed that ACSM5 was significantly down-regulated in HCC tumor tissues compared with non-tumor tissues. ACSM5 expression was regulated by DNA methylation, with a DNA methyltransferase 1 (DNMT1) inhibitor effectively increasing ACSM5 expression and reducing promoter region methylation. Overexpression of ACSM5 in Huh7 cells reduced fatty acid accumulation, decreased cell proliferation, migration, and invasion in vitro, and inhibited tumor growth in mouse xenografts. Furthermore, ACSM5 overexpression also decreased STAT3 phosphorylation, subsequently affecting downstream cytokine TGFB and FGF12 mRNA levels. These findings suggest that ACSM5 down-regulation contributes to HCC progression, providing insights into its oncogenic role and highlighting its potential as a biomarker and therapeutic target for HCC.