Project Summary/Abstract Peroxiredoxin 6 (Prdx6) is a multi-functional enzyme that expresses glutathione peroxidase, phospholipase A2, and lysophosphatidylcholine acyltransferase activities in separate catalytic sites. Prdx6 can reduce phospholipid hydroperoxides and hydrolyze and re-acylate phospholipid fatty acyl bonds. Prdx6 is, therefore, a complete enzyme for the repair of peroxidized cell membranes. Our lab studies the contributions of the different catalytic activities of Prdx6 to the suppression of ferroptosis, an iron-dependent form of regulated cell death driven by the accumulation of phospholipid hydroperoxides. Ferroptosis is implicated in ischemia/reperfusion (I/R) injury, but the role of Prdx6 in this process is unknown. Here, we propose studying how Prdx6 regulates ferroptosis in cellular renal I/R models. Renal I/R is the most prevalent cause of acute kidney injury, a clinically impactful disease that significantly affects patient management regarding the treatment options for their primary disease. We will use flow-adapted endothelial cells and kidney organoids derived from Prdx6 KO and KI mice carrying single point mutations that inactivate each of the Prdx6 activities alone to study how Prdx6 regulates oxidant stress, ferroptosis, and inflammatory signaling in renal I/R while providing postdoctoral training to Dr. Justin Conner who seeks to expand his skills and become a competitive candidate for a MOSIAC K99/R00 application in next two years, with the ultimate goal to become an independent biomedical investigator.