2. Academic Validation
  3. IFI16 is essential to linking DNA damage and ferroptosis in acute kidney injury

IFI16 is essential to linking DNA damage and ferroptosis in acute kidney injury

  • Cell Death Dis. 2026 Mar 23;17(1):350. doi: 10.1038/s41419-026-08604-5.
Zhe Qiao 1,  Di Zhou 1,  Tianxing Zhang 1,  Hongshen Lu 1,  Tongxin Ren 1,  Meng Jia 1,  Zhuhan He 1,  Yongqi Han 1,  Cuicui Lu 2,  Jichao Wu 1,  Min Liu 1,  Yu Sun 1,  Ziying Wang 1,  Yi Lu 3,  Wei Tang 4 5,  Fan Yi 6 7
Affiliations

Affiliations

  • 1 The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
  • 2 Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China.
  • 4 The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China. [email protected].
  • 5 Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, China. [email protected].
  • 6 The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China. [email protected].
  • 7 National Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, China. [email protected].
PMID: 41872158 DOI: 10.1038/s41419-026-08604-5
Abstract

Emerging evidence demonstrates the important role of Ferroptosis, a novel regulated cell death, in the initiation and progression of acute kidney injury (AKI). However, the activation mechanism of Ferroptosis in AKI has not been fully revealed. The pivotal function of interferon inducible protein 16 (IFI16) in DNA damage response (DDR) as DNA sensor and regulator of cell death pathways encouraged us to examine its role in Ferroptosis of renal tubular epithelial cells (TECs) in AKI. Here we report that the levels of IFI16 and its mouse ortholog p204 were elevated in the kidney of patients with acute tubular necrosis (ATN) and in TECs of mice with renal ischemia/reperfusion (I/R)-induced AKI (I/R-AKI). Under I/R conditions, tubule-specific p204 deficiency in mice and IFI16 knockout in HK-2 cells significantly ameliorated TEC Ferroptosis. Mechanistically, IFI16 binds to poly(ADP-ribose) polymerase 1 (PARP-1) and enhances protein Poly ADP-ribosylation (PARylation), which in turn potentiates the ataxia-telangiectasia mutated (ATM)-p53 signaling contributing to lipid peroxidation and ferrous ion accumulation in TECs. In addition, IFI16-amplified DDR was dependent on its HIN and PYRIN domains. Thus, our findings provide a better understanding of a critical pathogenic axis linking DNA damage to Ferroptosis and suggest that targeting IFI16 may be an innovative therapeutic strategy for treating patients with AKI.

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