The ACSL family: Bridging fatty acid metabolism and cell death in cancer progression

Fatty acids (FAs) are indispensable for cellular homeostasis and centered in anabolic and catabolic pathways that are tightly governed by long-chain acyl-CoA synthetases (ACSLs). These enzymes drive fatty acid β-oxidation (FAO) to generate energy, remodel cell membrane phospholipid composition to dictate ferroptosis susceptibility, coordinate steroidogenesis and eicosanoid biosynthesis, and mediate metabolic reprogramming, thus acting as a central nexus between FAs metabolism and cell death. Dysregulation of ACSLs across malignancies fosters oncogenic dependency on metabolic reprogramming, influencing tumor progression, immune modulation, and therapy resistance, offering a rationale for anticancer therapeutic opportunities. Here, we delineate the decisive roles of ACSLs in the metabolic fate of FAs and cell death execution. We dissect their tumorigenic mechanisms through metabolic rewiring and cell death modulation, with an emphasis on ACSLs-mediated crosstalk between ferroptosis and cancer immunity. Furthermore, we discuss the potential of ACSLs-targeted agents in tumor therapy and the treatment of ferroptosis-associated pathologies, offering actionable insights for clinical translation.