Long-chain-fatty-acid--CoA ligase 4 (ACSL4) (ACSL4)

Long-chain-fatty-acid--CoA ligase 4 (ACSL4) is an enzyme that plays a pivotal role in lipid metabolism by catalyzing the conversion of free long-chain fatty acids, particularly arachidonic acid and adrenic acid, into their active CoA esters [1, 4]. This activation is a prerequisite for their incorporation into phospholipids, which are essential components of cellular membranes. ACSL4 is recognized as a key driver of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, because it enriches membranes with polyunsaturated fatty acids (PUFAs) that are highly susceptible to oxidation [2]. In oncology, ACSL4 is frequently overexpressed in various cancers, including breast and liver cancer, where it contributes to tumor progression and can serve as a biomarker for ferroptosis sensitivity [3]. Conversely, its deficiency is associated with X-linked intellectual disability, highlighting its importance in neurodevelopment [1]. Therapeutic strategies targeting ACSL4 include small molecule inhibitors like thiazolidinediones and experimental compounds, as well as RNA-based approaches (targeting ACSL4 mRNA) to modulate its expression in the context of cancer and inflammatory diseases [2, 3].

Other names

Acyl-CoA synthetase 4FACL4LACL4Long-chain acyl-CoA synthetase 4ACSL4 mRNA

Inhibition of the enzymatic conversion of polyunsaturated fatty acids into fatty acyl-CoA, preventing their incorporation into membrane phospholipids and subsequent lipid peroxidation [2]. For RNA-targeting approaches, the mechanism involves the degradation of ACSL4 mRNA or inhibition of its translation to reduce protein levels [3].