ACSL1 catalyzes the conversion of long-chain fatty acids into their active form, acyl-CoA, facilitating both lipid synthesis and beta-oxidation. The enzyme preferentially activates palmitoleate, oleate, linoleate, and arachidonate and is localized to both the endoplasmic reticulum and mitochondria, where its subcellular location determines metabolic fate. ACSL1 expression is dynamically regulated in response to metabolic stress and circadian disruption. In disease contexts, ACSL1 has been implicated in multiple pathways: during circadian disruption in sleep-deficient conditions, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce palmitoyl-CoA, which sustains cancer stemness 1. In Alzheimer's disease with APOE4/4 genotype, ACSL1-positive microglia accumulate lipid droplets in response to fibrillar amyloid-beta, promoting neurotoxic effects 2. In diabetic nephropathy, the PRMT6/STAT1/ACSL1 axis promotes ferroptosis by upregulating ACSL1 expression, with STAT1 inhibitor fludarabine showing potential to delay disease progression 3. In myocardial ischemia-reperfusion injury associated with hyperlipidemia, ACSL1 upregulation drives lipid peroxidation and thromboinflammation through the LPC/LPA metabolic axis, making ACSL1 inhibition a potential therapeutic target 4. Ergosterol directly binds ACSL1 to promote mitochondrial fatty acid oxidation and reduce hepatic steatosis 5. These findings establish ACSL1 as a context-dependent metabolic hub connecting lipid metabolism to cancer, neurodegeneration, and cardiovascular disease.