ACSL6 (acyl-CoA synthetase long chain family member 6) primarily catalyzes the conversion of long-chain fatty acids to acyl-CoA for cellular lipid synthesis and beta-oxidation, with particular importance in brain fatty acid metabolism 1. Beyond its metabolic function, ACSL6 exhibits diverse roles in disease pathogenesis. In cancer, ACSL6 demonstrates context-dependent effects: it acts as a tumor suppressor in most cancers through downregulation, except in colorectal cancer 1. However, in liver cancer, ACSL6 promotes tumor progression and immune evasion by functioning as an adaptor protein that activates IL-18-NF-κB signaling, independent of its enzymatic activity 2. In cardiovascular disease, ACSL6 serves as a genetic determinant of diastolic function, with its expression correlating with mitochondrial function and contributing to sex differences in heart failure with preserved ejection fraction 3. ACSL6 also plays a role in ferroptosis regulation, where it mediates cell death through the circBNC2/miR-4298/ACSL6 axis in prostate cancer 4. Additionally, ETV6-ACSL6 fusion genes in hematopoietic malignancies are associated with severe eosinophilia and poor prognosis 5. These findings highlight ACSL6's dual metabolic and non-metabolic functions across multiple disease contexts.