# HDAC4 drives ferroptosis and fibrosis by inhibiting Foxo3a-GPX4 axis during AKI–CKD progression

## TL;DR

HDAC4 promotes kidney damage and scarring after injury by blocking a protective pathway, suggesting new treatment strategies.

## Contribution

Identifies HDAC4 as a key driver of ferroptosis and fibrosis in AKI–CKD progression via the Foxo3a-GPX4 axis.

## Key findings

- HDAC4 inhibition reduces ferroptosis and fibrosis in ischemia–reperfusion kidney injury.
- HDAC4 sequesters Foxo3a in the cytoplasm, reducing GPX4 transcription and increasing lipid peroxidation.

## Abstract

Histone deacetylase 4 (HDAC4) modifies both histone and non-histone proteins, but its role in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains unclear. Here, we investigated the function and mechanism of HDAC4 in ischemia–reperfusion (IR)–induced AKI–CKD progression using Tasquinimod, a highly selective HDAC4 inhibitor, and conditional tubular HDAC4 knockout mice. We found that HDAC4 expression was persistently upregulated after IR and was associated with sustained ferroptosis. Both pharmacological inhibition and tubular deletion of HDAC4 suppressed ferroptosis, alleviated tubular injury, and reduced fibrosis. Mechanistically, HDAC4 promoted ferroptosis by regulating the nucleocytoplasmic shuttling of Foxo3a: it enhanced Foxo3a phosphorylation, bound Foxo3a in the cytoplasm, and induced its deacetylation, collectively sequestering Foxo3a in the cytoplasm and reducing GPX4 transcription. Inhibition or deletion of HDAC4 restored Foxo3a nuclear localization, upregulated GPX4, and decreased lipid peroxidation. These findings identify HDAC4 as a key mediator linking IR injury to ferroptosis and fibrotic progression, suggesting that targeting the HDAC4–Foxo3a axis may provide a novel therapeutic strategy to prevent the AKI–CKD transition.