Acyl-CoA Synthetase Long-Chain Isoenzymes in Kidney Diseases: Mechanistic Insights and Therapeutic Implications

Long-chain acyl-CoA synthetases (ACSLs) are pivotal enzymes in fatty acid metabolism, essential for maintaining cellular homeostasis and energy production. Recent research has uncovered their significant involvement in the pathophysiology of various kidney diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), and renal cell carcinoma (RCC). While ACSL1, ACSL3, ACSL4, and ACSL5 have been extensively studied for their roles in processes such as ferroptosis, lipid peroxidation, renal fibrosis, epithelial-mesenchymal transition, and tumor progression, the role of ACSL6 in kidney diseases remain largely unexplored. Notably, these isoenzymes exhibit distinct functions in different kidney diseases. Therefore, to provide a comprehensive understanding of their involvement, this review highlights the molecular pathways influenced by ACSLs and their roles in modulating cell death, inflammation, and fibrosis during kidney disease progression. By examining these mechanisms in detail, this review underscores the potential of ACSLs as biomarkers and therapeutic targets, advocating for further research to elucidate the precise roles of individual ACSL isoenzymes in kidney disease progression. Understanding these mechanisms opens new avenues for developing targeted interventions and improving therapeutic outcomes for patients with kidney diseases. Trial RegistrationNA.Significance StatementCurrently, targeting ACSLs has shown beneficial results in various types of diseases; however, the knowledge about their role in the progression of kidney disease remains limited. Mechanistically, these isoenzymes are significantly involved in the progression of kidney disease. The significance of targeting ACSLs in kidney diseases is based on their specific roles in lipid metabolism, inflammation, and mitochondrial function. Therefore, considering the type of kidney disease, a highly involved ACSL isoenzyme can be targeted in the future to improve patient outcomes in kidney disease.