SLC27A3 encodes very long-chain acyl-CoA synthetase 3, a fatty acid transporter that functions as an acyl-CoA ligase catalyzing ATP-dependent activation of long-chain and very-long-chain fatty acids 1. The protein mediates cellular fatty acid levels by facilitating their transport across membranes and is expressed in neural stem cells during central nervous system development 2. Disruption of SLC27A3 function has broad clinical implications. Biallelic nonsense variants cause neurodegeneration with brain iron accumulation (NBIA), featuring progressive ataxia, neuropathy, optic atrophy, cognitive decline, and impaired mitochondrial respiration 3. At the population level, SLC27A3 loss-of-function variants associate with reduced asthma risk 4, while aberrant DNA methylation at SLC27A3 contributes to diabetic kidney disease progression 5. SLC27A3 upregulation correlates with chr1 obstructive pulmonary disease (COPD) severity, promoting Th17/Treg imbalance and lung inflammation via JAK2/STAT3 pathway activation 6. Additionally, SLC27A3 appears as a diagnostic biomarker in COPD with associations to immune cell infiltration 7, and rare height-associated variants in this gene show different selective pressures between populations 8. Depression susceptibility may involve SLC27A3 through methylation and expression changes 9. These findings position SLC27A3 as a critical regulator of lipid metabolism with implications for neurological, metabolic, respiratory, and immunological diseases.