SLC27A5 (FATP5) functions as a dual-role metabolic enzyme involved in fatty acid transport and bile acid metabolism in the liver. As a bile acyl-CoA synthetase, SLC27A5 catalyzes the ATP-dependent formation of bile acid CoA thioesters from primary and secondary bile acids, which is essential for bile acid reconjugation during enterohepatic recycling 1. The protein also facilitates long-chain fatty acid transport across cell membranes and catalyzes fatty acyl-CoA formation from long-chain and very-long-chain fatty acids. Loss of SLC27A5 leads to accumulation of unconjugated bile acids, particularly cholic acid, which activates hepatic stellate cells and promotes liver fibrosis 2. In hepatocellular carcinoma (HCC), SLC27A5 acts as a tumor suppressor through both metabolic and non-metabolic mechanisms. SLC27A5 deficiency increases lipid peroxidation, activating the NRF2/TXNRD1 pathway 3, and promotes sorafenib resistance by downregulating glutathione reductase 4. Additionally, SLC27A5 exhibits non-canonical functions by regulating alternative splicing of PIP4K2A pre-mRNA through interaction with IGF2BP3, thereby suppressing HCC metastasis 5. Hypoxic conditions reduce SLC27A5 expression via HNF4A suppression, promoting cell cycle progression 6. The SREBF1-SLC27A5 axis governs antioxidant responses and liver recovery in alcoholic liver disease 7.