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Endoplasmic reticulum stress mediates tubular epithelial cells ferroptosis in ischemic renal injury by activating Hilpda

ABSTRACT: Ischemia reperfusion injury (IRI) is a critical driver of acute kidney injury (AKI) and long-term renal dysfunction, yet the underlying mechanisms remain incompletely understood. This study investigates the role of endoplasmic reticulum (ER) stress in renal IRI and the underlying molecular mechanisms. Using a murine IRI model, we observed robust activation of ER stress pathways and pharmacological inhibition of ER stress significantly attenuated renal injury. Notably, ferroptosis related signatures, including upregulation of ferroptosis associated genes, iron overload, and lipid peroxidation, were significantly elevated in IRI damaged kidneys. Mechanistically, we identified activation of the IRE1α/XBP1 signaling axis, leading to the production of spliced XBP1 (XBP1s). Through luciferase reporter gene and electrophoretic mobility shift assay (EMSA), we identified that XBP1s directly binds to the promoter of Hilpda (Hypoxia-Inducible Lipid Droplet-Associated protein), driving its expression and promoting ferroptosis, thereby exacerbating renal damage. Our findings uncover a novel IRE1α/XBP1-Hilpda axis that links ER stress to ferroptosis in IRI, offering potential therapeutic targets for ameliorating acute kidney injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE298100 | GEO | 2026/09/30

REPOSITORIES: GEO

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