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

  • Free Radic Biol Med. 2025 Oct 10:242:9-20. doi: 10.1016/j.freeradbiomed.2025.10.256.
Yingying Zhang  1 ,  Hao Huang  2 ,  Nannan Li  1 ,  Yi Dong  3 ,  Meifang Zhao  3 ,  Siyuan Zhang  4 ,  Wenzhe She  3 ,  Jishi Liu  5 ,  Rong Xiang  6
Affiliations
  • 1. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China.
  • 2. Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China.
  • 3. Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China.
  • 4. Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China.
  • 5. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China; Hunan Critical Nephropathy Clinical Research Center, Changsha, China. Electronic address: [email protected].
  • 6. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China. Electronic address: [email protected].
PMID: 41077100 DOI: 10.1016/j.freeradbiomed.2025.10.256
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.

Keywords
Acute kidney injury; Ferroptosis; HSC70; Ischemia-reperfusion injury; RTN3.
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