The regulation and functions of ACSL3 and ACSL4 in the liver and hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a heterogeneous disease that often features dysregulated tumour lipid metabolism. ACSL3 and ACSL4 are two homologous long chain acyl-coenzyme A synthetases (ACSL) that preferentially catalyse the activation of monounsaturated and polyunsaturated fatty acids, respectively. Both enzymes are frequently overexpressed in HCC, and multiple reports have implicated ACSL4 in tumour progression. Increased expression of these isozymes in tumour cells can upregulate lipid metabolism through de novo lipogenesis, fatty acid β-oxidation and acyl chain remodelling of membrane phospholipids. We describe the subcellular functions of ACSL3 and ACSL4 in hepatocytes, and the transcriptional, epigenetic and post-translational mechanisms underpinning their regulation. We discuss the evidence that these enzymes can modulate hepatocarcinogenic signalling by oncoproteins, cell death by apoptosis or ferroptosis, and protein degradation through the ubiquitin-proteasome pathway. In addition, we survey how knowledge in this area may inform new approaches to the diagnosis and treatment of HCC and deepen our understanding of how lipid metabolic reprogramming can promote hepatic tumour growth.