ACSL5 (acyl-CoA synthetase long chain family member 5) is a mitochondrial and endoplasmic reticulum-localized enzyme that catalyzes the conversion of long-chain fatty acids to acyl-CoAs, primarily facilitating fatty acid β-oxidation rather than lipid synthesis 1. The enzyme shows preference for C16-C18 fatty acids and plays crucial roles in cellular energy metabolism 2. ACSL5 functions as a metabolic regulator in multiple tissues: in the liver, it prevents nonalcoholic fatty liver disease by promoting fatty acid oxidation when deacetylated by SIRT6 1, and its stabilization by USP29 through K48 deubiquitination protects against metabolic dysfunction-associated steatotic liver disease 3. In intestinal stem cells, ACSL5 is essential for renewal through HNF4-mediated transcriptional regulation of fatty acid oxidation genes 2. Intestine-specific ACSL5 deficiency increases postprandial GLP-1 and PYY secretion, reducing food intake and protecting against diet-induced obesity 4. In cancer, ACSL5 generally functions as a tumor suppressor, enhancing MHC-I-mediated antigen presentation and sensitizing tumors to immunotherapy 5, though its role varies by cancer type 6. The enzyme has been implicated in hepatocellular carcinoma progression through the PPARGC1A/BAMBI/ACSL5 axis 7 and identified as a potential ALS risk gene 8.