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This study investigates how the HDAC1 inhibitor FK228 affects renal ischemia-reperfusion injury by targeting specific molecular pathways.

May 14, 2026Cell Biology and Toxicology0 citationsOpen Access

The HDAC1 inhibitor attenuates renal ischemia–reperfusion injury via dual epigenetic modulation of p53 and macrophage NF-κB pathways

QZQian-Qian ZhangChinese Academy of Medical Sciences & Peking Union Medical College CYChen-Zhen YuChinese Academy of Medical Sciences & Peking Union Medical College FYFei-Hong YuChinese Academy of Medical Sciences & Peking Union Medical College

Key Points

This study investigates how the HDAC1 inhibitor FK228 affects renal ischemia-reperfusion injury by targeting specific molecular pathways.
Utilized IRI animal models and in vitro culture systems of tubular epithelial cells and bone marrow-derived macrophages.
Employed immunological and molecular biology techniques to assess cell apoptosis, repair, and macrophage activity.
Visualized key molecular interactions using confocal microscopy.
FK228 showed renoprotection in IRI, modulating p53 to inhibit apoptosis with a key role in the P53-Caspase-3 pathway.
Inhibition of the HDAC1-HIF-1α-NF-κB axis suppressed macrophage polarization, delaying fibrosis progression.
Confocal microscopy revealed reduced nuclear co-localization of phosphorylated NF-κB p65 and HIF-1α upon FK228 treatment.

Abstract

BACKGROUND: The renal regenerative capacity hinges on tubular epithelial cell (TEC) plasticity, while Macrophage activation and their crosstalk with tubular cells further drive ischemia-reperfusion injury (IRI) progression, where epigenetic regulation critically directs cellular fate. Based on the established association between HDAC dysregulation-specifically HDAC1-and renal injury, we investigated the therapeutic strategies and and epigenetic regulatory mechanisms underlying mechanisms of the selective HDAC1 inhibitor FK228 in renal IRI. METHODS: This study employed IRI animal models, along with in vitro culture systems of TECs and bone marrow-derived macrophages (BMDMs). A range of immunological and molecular biology techniques was used to assess TEC apoptosis and repair, as well as macrophage migration and polarization, with key molecular changes and their interactions visualized, too. RESULTS: Our findings demonstrate that FK228 confers renoprotection in renal IRI through HDAC1-dependent modulation of p53 activity, coordinating the regulation of apoptotic pathways (P53-Caspase-3) and proliferative responses in tubular epithelium while attenuating oxidative stress and modulating macrophage crosstalk. And beyond that, FK228 delays IRI progression and fibrosis by inhibiting the HDAC1-HIF-1α-NF-κB signaling axis, thereby suppressing morphological transformation and limiting macrophage proliferation and differentiation. Confocal microscopy revealed that FK228 redistributes phosphorylated NF-κB p65 and HIF-1α to the cytoplasm while reducing their nuclear co-localization. CONCLUSION: In conclusion, This study demonstrates that FK228 protects TECs from IRI by modulating the p53-Caspase-3/Bcl-2 pathway to inhibit apoptosis. Additionally, FK228 targets the HDAC1-HIF-1α-NF-κB axis to suppress pathological macrophage polarization, thereby delaying renal fibrosis and ameliorating both acute injury and its chronic progression.

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Zhang et al. (Mon,) studied this question.

synapsesocial.com/papers/6a05659da550a87e60a1dedd https://doi.org/https://doi.org/10.1007/s10565-026-10202-2

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