# Therapeutic Potential of CHCHD2 in Ischemia–Reperfusion Injury: Mechanistic Insights into Nrf2-Dependent Antioxidant Defense in HK2 Cells

## TL;DR

This study shows that CHCHD2 protects kidney cells from injury by boosting antioxidant defenses through the Nrf2 pathway, suggesting it could be a treatment for acute kidney injury.

## Contribution

The study reveals a novel mechanism by which CHCHD2 mitigates ischemia-reperfusion injury via Nrf2-dependent antioxidant activation in HK2 cells.

## Key findings

- CHCHD2 overexpression reduces ROS, lipid peroxidation, apoptosis, KIM-1, and NGAL in ATP-D/R injury.
- CHCHD2 activates Nrf2, promoting nuclear translocation and upregulation of HO-1, an antioxidant enzyme.
- Nrf2 knockdown diminishes the protective effects of CHCHD2, confirming its role in the cytoprotective mechanism.

## Abstract

Acute kidney injury (AKI) resulting from ischemia/reperfusion (I/R) poses a significant clinical challenge due to its high mortality and complex pathophysiology. Here, the protective actions of Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced adenosine triphosphate depletion and recovery (ATP-D/R) injury in human kidney-2 (HK2) cells are examined. During ATP-D/R, expression levels of CHCHD2 were significantly reduced. The overexpression of CHCHD2 substantially reduced the levels of ROS, lipid peroxidation, apoptosis, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), whereas the knockdown of CHCHD2 exacerbated cellular injury. Mechanistic studies further demonstrated that overexpression of CHCHD2 restored Nrf2 expression under ATP-D/R conditions, facilitated its nuclear translocation, and upregulated the downstream antioxidant enzyme HO-1. In contrast, the knockdown of Nrf2 reduced the cytoprotective actions of CHCHD2. These findings indicate that CHCHD2 reduces cellular damage by enhancing antioxidant defenses and reducing apoptosis through activating the Nrf2 axis, underscoring its potential as a therapeutic target for AKI.