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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p> Graphical Abstract <p>This schematic summarizes the mechanism by which FK228, an HDAC1 inhibitor, regulates renal injury and repair following IRI. IRI induces aberrant p53 acetylation in TECs, leading to activation of the Caspase-3-mediated apoptotic pathway and recruitment of macrophages, which exacerbates tissue damage. In the sustained IRI microenvironment, M1 macrophages promote M2 polarization, macrophage-myofibroblast transition (MMT), and subsequent fibrosis by releasing inflammatory cytokines via NF-κB p65 phosphorylation and nuclear translocation, along with activation of HIF-1α signaling. FK228 restores the balance of p53 acetylation through HDAC1 inhibition, thereby reducing apoptosis and mitigating macrophage-mediated injury. Concurrently, FK228 blocks NF-κB p65 phosphorylation and nuclear translocation, restores p65 acetylation levels, and diminishes its nuclear co-localization with HIF-1α, ultimately suppressing macrophage polarization and delaying fibrosis. Red arrows indicate pro-inflammatory or pro-fibrotic pathways, while green T-bars denote the inhibitory effects of FK228.</p> <p>• FK228 confers dual protection against IRI-induced acute kidney damage, subsequent renal fibrosis.</p> <p>• FK228 alleviates macrophage migration and tubular apoptosis by modulating the caspase-3 pathway via acetylation-dependent p53 regulation of the Bcl-2 family.</p> <p>• FK228 protects against IRI-induced renal impairment and fibrosis by reducing mononuclear cell infiltration and suppressing the expansion of M1, M2, and MMT cells.</p> <p>• FK228 altered NF-κB p65 modifications and diminished its cytoplasmic co-localization with HIF-1α in activated macrophages, subsequently modulating their polarization.</p> <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Qian-Qian Zhang,
  • Chen-Zhen Yu,
  • Fei-Hong Yu,
  • Yong-Bo Wang,
  • Song Chen,
  • Zhong-Hua Klaus Chen,
  • Wei-Jie Zhang,
  • Sheng Chang

摘要

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.

Graphical Abstract

This schematic summarizes the mechanism by which FK228, an HDAC1 inhibitor, regulates renal injury and repair following IRI. IRI induces aberrant p53 acetylation in TECs, leading to activation of the Caspase-3-mediated apoptotic pathway and recruitment of macrophages, which exacerbates tissue damage. In the sustained IRI microenvironment, M1 macrophages promote M2 polarization, macrophage-myofibroblast transition (MMT), and subsequent fibrosis by releasing inflammatory cytokines via NF-κB p65 phosphorylation and nuclear translocation, along with activation of HIF-1α signaling. FK228 restores the balance of p53 acetylation through HDAC1 inhibition, thereby reducing apoptosis and mitigating macrophage-mediated injury. Concurrently, FK228 blocks NF-κB p65 phosphorylation and nuclear translocation, restores p65 acetylation levels, and diminishes its nuclear co-localization with HIF-1α, ultimately suppressing macrophage polarization and delaying fibrosis. Red arrows indicate pro-inflammatory or pro-fibrotic pathways, while green T-bars denote the inhibitory effects of FK228.

• FK228 confers dual protection against IRI-induced acute kidney damage, subsequent renal fibrosis.

• FK228 alleviates macrophage migration and tubular apoptosis by modulating the caspase-3 pathway via acetylation-dependent p53 regulation of the Bcl-2 family.

• FK228 protects against IRI-induced renal impairment and fibrosis by reducing mononuclear cell infiltration and suppressing the expansion of M1, M2, and MMT cells.

• FK228 altered NF-κB p65 modifications and diminished its cytoplasmic co-localization with HIF-1α in activated macrophages, subsequently modulating their polarization.