ACSL1 (acyl-CoA synthetase long chain family member 1) catalyzes the conversion of long-chain fatty acids to their active acyl-CoA form, primarily facilitating fatty acid oxidation and lipid synthesis 123. The enzyme shows preference for palmitoleate, oleate, and linoleate, with subcellular localization to mitochondria and endoplasmic reticulum determining metabolic fate 34. During fasting, TBK1 scaffolds ACSL1 to mitochondria to promote β-oxidation, while in obesity-related states, ACSL1 shifts toward endoplasmic reticulum-mediated fatty acid re-esterification 4. ACSL1 dysfunction contributes to multiple pathologies: nonalcoholic steatohepatitis through impaired fatty acid oxidation and autophagy 5, circadian disruption-enhanced lung tumorigenesis via PA-CoA-mediated CLOCK palmitoylation 6, Alzheimer's disease microglia lipid droplet accumulation in APOE4/4 carriers 7, and diabetic nephropathy ferroptosis via the PRMT6/STAT1/ACSL1 axis 8. In cancer, ACSL1 promotes TNFα-mediated pro-inflammatory progression 9, while in myocardial ischemia-reperfusion injury, ACSL1 upregulation drives thromboinflammation through LPC/LPA metabolic reprogramming 10. Therapeutic modulation through ergosterol allosteric activation shows promise for alleviating hepatic steatosis 11. These findings establish ACSL1 as a critical metabolic hub linking fatty acid activation to diverse pathophysiological processes.