Tubular ACSM3 controls fatty acid metabolism and safeguards against acute kidney injury in male mice.

Kidney tubular epithelial cells exceptionally exhibit high energy demands and preferentially metabolize long-chain fatty acids via fatty acid oxidation (FAO), where the impairment of FAO represents a hallmark of acute kidney injury (AKI). However, the role of medium-chain fatty acid metabolism in kidney injury remains unexplored. Here, we identify that tubular acyl-CoA synthetase medium-chain family member 3 (ACSM3), the key enzyme responsible for medium-chain fatty acid activation, is significantly down-regulated in damaged kidneys of distinct AKI male mouse models and acute tubular necrosis patients. Unexpectedly, tubule-specific ACSM3 deletion improves renal dysfunction, pathological damage, and metabolic disturbances in AKI male mice. Mechanistically, tubular ACSM3 deficiency preserves free fatty acid pool and reduces medium-chain fatty acids utilization, where these unused medium-chain fatty acids as ligands can activate peroxisome proliferator-activated receptor alpha (PPARα) and further upregulate PPARα-associated fatty acid metabolic genes to repair injured kidneys. Notably, dietary supplementation of medium-chain fatty acids confers protective effects against AKI in male mice. Our findings highlight tubular ACSM3 as a potential therapeutic target to control renal fatty acid metabolism and provide preclinical evidence that medium-chain fatty acid supplementation safeguards against AKI.