ABSTRACT Acute kidney injury (AKI) most commonly occurs in the hospital setting. Hospital-acquired AKI accounts for 22% of all cases worldwide, and nearly 50% of critically ill inpatients are estimated to suffer from AKI. AKI is associated with high rates of morbidity and mortality, and causes 2 million deaths per year. The hospitalization cost of AKI treatment in the US per year is approximately 24 billion. While the kidney may recover, the patients are at a higher risk for subsequently developing chronic kidney disease (CKD). Other times, the acute injury is so severe that there is no kidney recovery and ultimately end stage renal disease (ESRD) ensues. Patients that progress to CKD have hospitalization costs of approximately 100 billion dollars a year in the US. A definitive and effective treatment for AKI is still lacking, nor are there available interventions to decrease the risk of progression to CKD after AKI. Current strategies focus on prevention, early diagnosis, and early interventions aimed at managing the underlying etiologies and complications of AKI. Metabolic signaling during AKI has emerged as an exciting and potentially druggable target to not only reverse but inhibit proximal tubule damage associated with AKI and block the subsequent progression to CKD. The majority of metabolic studies in the literature have focused on protecting the mitochondria, which are known to be damaged during AKI. However, we recently showed that boosting peroxisomal fatty acid oxidation (FAO) protects against injury in two different mouse models of AKI. Here, we exploited this protective mechanism by supplementing the diet with peroxisomally-targeted medium- chain dicarboxylic fatty acids (DCAs). In ischemia/reperfusion injury and nephrotoxic (cisplatin) mouse AKI models, 7 days of dietary supplementation with an 8-carbon DCA called octanedioc acid (DC8) dramatically reduced kidney injury and improved function (Similar protection was seen with DC12). We recapitulated the injury model in vitro, where DCAs conferred protection to human renal proximal tubule epithelial cells (RPTECs). We propose that DCA is activated to coenzyme-A to form DCA-CoA, which undergoes two rounds of FAO chain- shortening in peroxisomes to produce DC4-CoA, also known as succinyl-CoA. Peroxisomal succinyl-CoA maintains high peroxisomal FAO enzyme activity via induction of a post-translational modification (PTM) called lysine succinylation. Further, peroxisomal FAO enzyme activity hydrolyzes succinyl-CoA to succinate, which is exported to mitochondria where it drives ATP synthesis through Complex II of the respiratory chain. We hypothesize that this “quick energy” bolsters the kidney against injury, promoting recovery and limiting progression to CKD. We expect that DCA metabolically shields the kidney against AKI via peroxisome- mitochondria metabolic crosstalk this proposal will accelerate the clinical translation of DCA for AKI.