Abstract: SA-PO0158
Estrogen Metabolites Protect Against AKI by Regulating Ferroptosis Sensitivity
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Tonnus, Wulf, Technische Universitat Dresden, Dresden, SN, Germany
- Linkermann, Andreas, Universitatsklinikum Mannheim, Mannheim, BW, Germany
Background
Epidemiological studies suggested that premenopausal women suffer fewer episodes of acute kidney injury (AKI) than males, and that estrogen (E2) supplementation protects concomitantly. However, molecular mechanisms of this phenomenon remain ill-defined. As ferroptosis, an iron-dependent form of regulated necrosis, plays a crucial role in the pathogenesis of AKI, we hypothesized that estrogens might be a ferroptosis-regulating factor controlling AKI susceptibility.
Methods
The effects of estrogens on ferroptosis sensitivity were investigated in a broad approach. Mechanistic insights were derived cell culture experiments levering complex pharmacological and genetic approaches. Radical trapping mechanisms were tested in cell free systems, whereas translational relevance was established via isolated renal tubules of various species including humans. Murine studies tested proposed mechanisms in AKI models.
Results
E2 protected against ferroptosis and associated lipid peroxidation in cell culture. Mechanistically, E2 quinone derivates 2OH and 4OH were identified as potent lipophilic radical trapping antioxidants, which were regenerated by the oxidoreductase FSP1 (AIFM2). Interestingly, inhibition of FSP1 sensitized cells to ferroptosis in an E2-dependent manner. Furthermore, we identified several E2-induced antiferroptotic programs via the ESR1 including higher generation of hydropersulfides, and downregulation of ether lipids via reduced AGPS expression. Knock-out studies confirmed the functional relevance of these mechanisms, whereas isolated tubuli from several mammalian species demonstrated the conservation of these mechanisms throughout evolution. Studies utilizing the murine IRI model proved the functional relevance of these mechanisms upon AKI.
Conclusion
In summary, we describe the molecular underpinnings of ferroptosis resistance in female mammals. These findings may explain epidemiological data on female resistance to AKI, and could lead the path to sex-specific interventions in prevention and treatment of human AKI.
Funding
- Government Support – Non-U.S.