Glucocorticoid Receptor Attenuates Epithelium Ferroptosis and AKI via IDO2-Mediated Signaling, a Tryptophan Metabolism-Independent Pathway

Background: Acute kidney injury (AKI) is a life-threatening clinical disorder in which ferroptosis, a recently characterized form of regulated cell death, has been implicated as a pathogenic driver. Although dexamethasone-mediated renal protection has been extensively studied in the progression of kidney diseases, its specific role and mechanisms in renal tubular epithelial cells and acute kidney injury remain poorly defined. Methods: Immunohistochemical staining was used to evaluate the expression and localization of GR (Glucocorticoid Receptor) and phosphorylated GR in kidney biopsies from patients with AKI. Subsequently, conditional KO mice in which GR gene was selectively ablated in proximal tubular cells were generated. We then investigated the contributions of tubular GR signaling to AKI by assessing kidney injury parameters, analyzing RNA-sequencing data, and assessing ferroptosis-related biomarkers in both the cisplatin-and ischemic-reperfusion injury(IRI)-induced AKI. Human renal tubular cell line HK-2 was also employed to study the underlying mechanisms. Results: Tubular GR-associated signaling pathways were significantly upregulated in kidney biopsy specimens with AKI. GR activation in the proximal tubule attenuated cisplatin- and IRI-induced AKI and renal tubular ferroptosis through upregulation of IDO2/GPX4 signaling. By contrast, IDO2 mitigated ferroptosis and AKI through a tryptophan metabolism-independent mechanism. Moreover, treatment with the ferroptosis inhibitor, Ferrostatin-1, rescued cisplatin-induced AKI in KO mice. In vitro gain- and loss-of-function experiments affecting GR established that GR/IDO2/GPX4 axis plays an important role in regulating tubular cell ferroptosis and cell death. Mechanistically, GR directly bound to the promoter of IDO2 and drove its expression. The upregulated IDO2 protein stabilized GPX4 through suppression of ubiquitin-dependent degradation, a process dissociated from tryptophan metabolism as validated by metabolomic analyses. Conclusion: This study establishes a previously unrecognized GR/IDO2/GPX4 axis that protects against tubular ferroptosis and AKI through a tryptophan metabolism-independent pathway. These mechanistic insights highlight this axis as a promising therapeutic target for AKI management that may circumvent glucocorticoid-related adverse effects. Funding: Government Support – Non-U.S.