# Targeting CDC42 Protects Mitochondrial Function through KLF2/HIF-1α/PINK1 Signaling in Acute Kidney Injury

## TL;DR

This study shows that targeting CDC42 helps protect kidney cells by improving mitochondrial function and reducing damage in acute kidney injury.

## Contribution

The study reveals a novel role of CDC42 in AKI and identifies a new therapeutic strategy through the KLF2/HIF-1α/PINK1 pathway.

## Key findings

- CDC42 inhibition reduces renal injury and preserves mitochondrial function in AKI models.
- CDC42 suppression activates a KLF2/HIF-1α/PINK1 cascade that promotes mitophagy and reduces oxidative stress.
- The KLF2/HIF-1α/PINK1 pathway is critical for protecting renal tubular epithelial cells from oxidative damage.

## Abstract

Acute kidney injury (AKI) is a severe clinical syndrome strongly associated with mitochondrial dysfunction and oxidative stress, yet effective therapies remain elusive. Here, we identify cell division cycle 42 (CDC42) as a critical mediator of AKI. Analysis of human single-cell RNA sequencing (scRNA-seq) dataset revealed marked upregulation of CDC42 in renal tubular epithelial cells (RTECs), which was validated in murine models of cisplatin- and ischemia-reperfusion-induced AKI. Pharmacological inhibition, conditional knockdown, or genetic ablation of CDC42 significantly alleviated renal injury, preserved mitochondrial function, and reduced reactive oxygen species (ROS) both in vivo and in vitro. Mechanistically, transcriptomic analysis, bioinformatic analysis, dual-luciferase reporter assays, ChIP assays and cellular functional validation revealed that CDC42 suppression activated a KLF2/HIF-1α/PINK1 transcriptional cascade, thereby promoting mitophagy and restoring mitochondrial homeostasis. Functional assays supported that this pathway plays a pivotal role in protecting RTECs from oxidative damage. Collectively, these findings uncover a previously unrecognized role of CDC42 in AKI pathogenesis and highlight CDC42 inhibition as a promising therapeutic strategy for mitigating mitochondrial damage and improving renal outcomes.