2. Academic Validation
  3. STING promotes ferroptosis through NCOA4-dependent ferritinophagy in acute kidney injury

STING promotes ferroptosis through NCOA4-dependent ferritinophagy in acute kidney injury

  • Free Radic Biol Med. 2023 Aug 25;S0891-5849(23)00605-6. doi: 10.1016/j.freeradbiomed.2023.08.025.
Lini Jin 1,  Binfeng Yu 2,  Hongju Wang 1,  Lingling Shi 1,  Jingjuan Yang 1,  Longlong Wu 1,  Cui Gao 1,  Hong Pan 1,  Fei Han 3,  Weiqiang Lin 4,  En Yin Lai 5,  Yong-Fei Wang 6,  Yi Yang 7
Affiliations

Affiliations

  • 1 Department of Nephrology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
  • 2 Department of Infectious Disease, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 3 Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Institute of Nephrology, Zhejiang University, Zhejiang, China; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China.
  • 4 Department of Nephrology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China. Electronic address: wlin@zju.edu.cn.
  • 5 Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Institute of Nephrology, Zhejiang University, Zhejiang, China; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China; Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Translational Physiology, Berlin, Germany. Electronic address: laienyin@zju.edu.cn.
  • 6 School of Life and Health Sciences, School of Medicine, Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, China. Electronic address: yfwang@cuhk.edu.cn.
  • 7 Department of Nephrology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China; International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China. Electronic address: yangyixk@zju.edu.cn.
PMID: 37634745 DOI: 10.1016/j.freeradbiomed.2023.08.025
Abstract

Ferroptosis in tubules has been implicated in the pathogenesis of acute kidney injury (AKI), whereas the regulatory mechanism remains unclear. The stimulator of interferon genes (STING) is previously recognized as a critical mediator of innate immunity via a DNA-sensing pathway and has been increasingly linked to lipid peroxidation, a hallmark of Ferroptosis. Herein we investigated the role and the underlying mechanism of STING in AKI models established by ischemia/reperfusion (IR) in C57BL mice. The expression level of STING was predominantly increased in tubules of kidney after IR treatment. Besides, STING deficiency markedly alleviated IR-induced lipid peroxidation, tissue damage and renal dysfunction. Consistently, in vitro experiments demonstrated that the increase in ferroptotic cell death, lipid ROS production and the decrease in GSH peroxidase 4 (GPX4) expression in renal tubular cells subjected to Ferroptosis agonist or hypoxia/reoxygenation intervention were all mitigated by genetic deficiency or pharmacological inhibition of STING, while all exacerbated by STING overexpression. Further, these detrimental effects of STING overexpression relied on the induction of ferritinophagy, i.e. autophagic degradation of ferritin, leading to iron overload. Mechanistically, STING mediated the initiation of ferritinophagy through interacting with nuclear receptor coactivator 4 (NCOA4), a fundamental receptor for the transfer of ferritin into lysosome. Collectively, STING contributes to Ferroptosis during ischemic AKI through facilitating NCOA4-mediated ferritinophagy and shows the potential as a promising therapeutic choice for AKI.

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