ACSM5 (acyl-CoA synthetase medium chain family member 5) is a mitochondrial enzyme that catalyzes the activation of fatty acids by CoA to produce acyl-CoA, representing the initial step in fatty acid metabolism 1. The enzyme localizes to the mitochondrial matrix and plays crucial roles in lipid metabolism regulation 2. ACSM5 demonstrates tumor suppressor properties across multiple cancer types. In hepatocellular carcinoma (HCC), ACSM5 is significantly downregulated due to DNA methylation by DNMT1, and its overexpression reduces fatty acid accumulation, decreases cell proliferation, migration, and invasion while inhibiting tumor growth 1. The protein induces ferroptosis in HCC cells by upregulating cytochrome P450 oxidoreductase (POR) and promoting conversion of linoleic acid to arachidonic acid, thereby increasing cellular sensitivity to ferroptosis 2. ACSM5 also functions as a suppressor in lumbar ligamentum flavum hypertrophy, where its hypermethylation-mediated downregulation promotes fibrosis and cell proliferation 3. Additionally, ACSM5 expression correlates with thyroid cancer susceptibility through m6A methylation mechanisms 4. The gene serves as a potential biomarker for various diseases and represents a promising therapeutic target, particularly in metabolic disorders and cancer treatment strategies.