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

## TL;DR

IFI16 connects DNA damage to ferroptosis in kidney injury, offering a new therapeutic target for acute kidney injury.

## Contribution

Identifies IFI16 as a key mediator linking DNA damage to ferroptosis in acute kidney injury.

## Key findings

- IFI16 and p204 levels increase in acute kidney injury and promote ferroptosis in renal cells.
- IFI16 enhances PARylation and activates ATM-p53 signaling, leading to lipid peroxidation and iron accumulation.
- Targeting IFI16 reduces ferroptosis and may serve as a novel treatment for AKI.

## 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.