Sex-specific Expression of Estradiol Derivatives, Hydropersulfides and Ether Lipids Regulates Ferroptosis Sensitivity of Kidney Tubules

Abstract Acute kidney tubular necrosis (ATN) mediates acute kidney injury (AKI) and nephron loss, the major risk factor for chronic kidney disease (CKD) progression and end-stage renal disease (ESRD) 1-3 . For decades, it has been known that female tissue is less sensitive to AKI 4,5 , but the underlying mechanisms have remained elusive. As a specific feature, ATN is characterized by dynamic cell death propagation along the tubular compartment, mediated by ferroptosis in male mice 6,7 . Herein we demonstrate that ferroptotic cell death propagation is abrogated in female kidney tubules. Ferroptosis sensitivity in females was decreased by estradiol and its derivatives, which function as radical-trapping antioxidants (RTAs). Female sex-specific tubular expression of ferroptosis suppressor protein 1 (FSP1, also AIFM2) functions to regenerate the estradiol derivatives from their oxidation products, thereby potentiating RTA capacity. In addition, females exhibited much higher levels of anti-ferroptotic hydropersulfides detected directly from the most sensitive tubular compartment. In contrast, male proximal tubules express alkylglycerone phosphate synthase (AGPS) and fatty acyl-CoA reductase 1 (FAR1), key enzymes required for the generation of ether lipids which sensitize to ferroptosis. In summary, we uncover three independent mechanisms that collectively explain higher ferroptosis sensitivity of male over female tubular tissue and may function as therapeutic targets.