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. Fatty acid oxidation impairment represents a hallmark of acute kidney injury (AKI). Here the authors report that tubular deficiency of ACSM3, an enzyme involved in medium chain fatty acid activation, is protective against kidney injury in male mouse models of AKI potentially via modulating PPARα activity.