Reticulon 3 deficiency induces ferroptosis via chaperone-mediated autophagy in ischemia-reperfusion induced acute kidney injury.

Abstract

Acute kidney injury (AKI) represents a critical clinical syndrome characterized by abrupt deterioration of renal function. Ischemia-reperfusion injury (IRI) constitutes the predominant etiology of AKI, where renal hypoperfusion triggers tubular epithelial cell death. While ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, has been implicated in AKI pathogenesis, its regulatory mechanisms remain elusive. Here, we identify reticulon 3 (RTN3), an endoplasmic reticulum-resident scaffolding protein, as a novel ferroptosis regulator in IRI-AKI models. Western blotting and immunohistochemistry revealed significant RTN3 downregulation in renal tissues following IRI. RTN3-deficient mice exhibited exacerbated renal dysfunction, pathological damage, and oxidative stress markers compared to wild-type controls. Mechanistically, RTN3 ablation promoted GPX4 degradation via chaperone-mediated autophagy (CMA). Co-immunoprecipitation demonstrated RTN3 physically interacts with HSC70, thereby limiting HSC70-mediated GPX4 translocation to lysosomes. This study unveils the RTN3-HSC70-GPX4 axis as a pivotal pathway governing ferroptosis in IRI-AKI, suggesting RTN3 agonism as a potential therapeutic strategy for ischemic renal injury.