Roles of ACSL6 in lipid homeostasis and stress responses in the nervous system

Acyl-CoA synthetase long-chain family member 6 (ACSL6) is a member of the long-chain acyl-CoA synthetase (ACSLs) family that is particularly expressed in nervous system. It mainly catalyzes the activation reaction of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA), providing substrates for the synthesis and remodeling of neuronal membrane lipids. Recent studies have shown that ACSL6 plays a decisive role in DHA enrichment, synaptic plasticity and antioxidant defense in the brain. Its dysfunction can lead to changes in membrane lipid composition, weakened synaptic signals and excessive activation of neuroinflammation, thereby causing neurological deficits like cognitive and motor disorders. This review comprehensively summarizes the molecular structure characteristics and catalytic mechanism of ACSL6, and analyzes the roles of its different domains in substrate recognition and reaction regulation. ACSL6 participates in lipid metabolism by converting DHA into DHA-CoA, forming a local DHA metabolic pathway and providing continuous energy supply for the structural stability and signal transmission of nerve membranes. The localization characteristics of ACSL6 enable the spatial directional distribution of DHA in the synaptic membrane and endoplasmic reticulum regions, which is a key link in maintaining brain lipid homeostasis. In addition, ACSL6 is involved in the defense mechanisms of the nervous system by regulating oxidative stress responses, ferroptosis and inflammatory pathways. Its dysregulation has been confirmed to be associated with various neurodegenerative diseases. A thorough clarification of the molecular mechanism of ACSL6 may provide a new theoretical basis and highlight potential avenues for future therapeutic exploration regarding the imbalance of lipid homeostasis in neurons and related diseases.