Ferroptotic Cell Death in Adrenal Inflammation and Septic Shock
Rapid release of adrenal stress hormones is essential for survival during sepsis, a life-threatening syndrome characterized by dysregulated host responses to infection and subsequent multiorgan dysfunction. Owing to their dense vascularization and the generation of reactive oxygen species during steroidogenesis, adrenal glands are particularly susceptible to sepsis-induced injury. Indeed, severe infections are frequently associated with adrenal hemorrhage, inflammation, infarction, and necrosis, which may contribute to adrenal insufficiency and poor clinical outcomes.
Recent evidence, including our own findings, suggests that regulated necrosis plays an important role in sepsis-induced organ damage. However, the mechanisms underlying adrenal cell death during sepsis remain incompletely understood. Our preliminary studies identified ferroptosis, an iron-dependent form of regulated necrosis driven by lipid peroxidation, as a major cell death pathway in adrenocortical cells. Pharmacological inhibition of glutathione peroxidase 4 (GPX4) in the human adrenocortical cell line NCI-H295R resulted in increased lipid peroxidation and necrotic cell death, which could be prevented by ferroptosis inhibitors. Preliminary data further suggest that similar mechanisms may operate in non-transformed adrenal tissue.
The aim of this project is to investigate the contribution of ferroptosis to sepsis-induced adrenal gland damage and dysfunction. Using established in vitro and ex vivo models including adrenal cell lines and primary mouse adrenal spheroids, the project will assess ferroptosis induction, characterize its molecular regulation, and evaluate the protective potential of ferroptosis-targeting interventions. Particular emphasis will be placed on the roles of GPX4, lipid peroxidation, and iron metabolism in maintaining adrenocortical cell viability under inflammatory conditions.
References:
-
Tonnus W, Maremonti F, Gavali S, Schlecht MN, Belavgeni A, et al. Multiple oestradiol functions inhibit ferroptosis and acute kidney injury. Nature. 2025;645:1011–1019.
-
Van Coillie S, Van San E, Goetschalckx I, Wiernicki B, Mukhopadhyay B, Tonnus W, et al. Targeting ferroptosis protects against experimental (multi)organ dysfunction and death. Nat Commun. 2022;13:1046.
-
Kanczkowski W, Evert K, Stadtmüller M, Haberecker M, Laks L, Chen LS, et al. COVID-19 targets human adrenal glands. Lancet Diabetes Endocrinol. 2022;10(6):437–446.
-
Tonnus W, Linkermann A. The role of regulated necrosis in endocrine diseases. Nat Rev Endocrinol. 2021;17(8):497–510.
-
Belavgeni A, Meyer C, Stumpf J, Hugo C, Linkermann A, et al. Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis. Proc Natl Acad Sci U S A. 2019;116(44):22269–22274.
- Art der Promotion
- Forschungssemester notwendig?
- Finanzierung/Anstellung
- Angeschlossen an ein strukturiertes Promotionsprogramm?
- Zeitplan
- 01.09.26
- Abteilung / Struktureinheit
- ein Dokument mit weiterführenden Informationen
Betreuung
- Erstbetreuung
- weitere Betreuende
Relevante/Repräsentative Publikation mit evtl. Vordaten
Methodik/Aufgaben
- Experimentell
- klinisch
- theoretisch
- statistisch
Bewerbung
- Bewerber:innen-Profil
- Benötigte Bewerbungsunterlagen