ACSM4 (acyl-CoA synthetase medium chain family member 4) is a mitochondrial enzyme that catalyzes the activation of medium-chain fatty acids (C6-12) to acyl-CoA, the initial step in fatty acid metabolism. Located in the mitochondrial matrix, ACSM4 functions as a fatty-acyl-CoA synthase in lipid metabolic pathways. Beyond its canonical metabolic role, ACSM4 expression levels have clinical significance in cancer prognosis. A two-gene prognostic signature incorporating ACSM4 and SPDYC was identified as independently associated with poor prognosis in triple negative breast cancer (TNBC) patients, with elevated ACSM4 expression correlating with worse distant metastasis-free survival and breast cancer-specific survival 1. This prognostic association was validated at both mRNA and protein expression levels. Genetic variation in ACSM4 also influences HIV disease progression. Specific ACSM4 polymorphisms (rs7137120 and rs7961991) and their associated haplotypes show significant association with rapid AIDS progression in untreated HIV-infected patients, with odds ratios ranging from 2.85 to 3.60 2. Additionally, ACSM4 was identified among nuclear-encoded mitochondrial genes with SNPs significantly associated with AIDS progression rate 3. These findings suggest ACSM4's mitochondrial function may influence immune pathogenesis and tumor biology through metabolic mechanisms.