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.