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PRDM5 regulates ASK1 transcription to affect macrophage inflammation, lipid accumulation and apoptosis progression

Mengchen Sun1, Han Sun1, Hanzheng Wang2

  • 1Qingdao Medical College, Qingdao University, Qingdao, 266071, China; Department of Cardiology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, 264000, China.

Experimental Cell Research
|August 19, 2026
PubMed
Abstract

Insights

PR domain zinc finger protein 5 (PRDM5) is a key genetic factor in atherosclerotic cardiovascular disease (ASCVD). It drives macrophage dysfunction and inflammation, contributing to systemic lesions, but can be targeted by ezetimibe.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Biology
  • Immunology

Background:

  • Atherosclerotic cardiovascular disease (ASCVD) exhibits shared genetic susceptibility across diverse vascular lesions.
  • Identifying common pathogenic factors for multi-territorial atherosclerosis is crucial.
  • PR domain zinc finger protein 5 (PRDM5) is hypothesized to regulate systemic atherosclerotic lesions by modulating monocyte-macrophage function.

Purpose of the Study:

  • To investigate PR domain zinc finger protein 5 (PRDM5) as a shared genetic regulator in atherosclerotic cardiovascular disease (ASCVD).
  • To elucidate the molecular mechanisms by which PRDM5 contributes to systemic atherosclerosis.
  • To evaluate the therapeutic potential of ezetimibe in targeting PRDM5-mediated pathways.

Main Methods:

  • Utilized multi-trait genome-wide association studies (GWAS) and genomic structural equation modeling (Genomic SEM) to identify shared ASCVD risk loci.
  • Performed transcriptome-wide association study (TWAS) in CD14+ monocytes to prioritize candidate genes.
  • Conducted cellular functional assays, ChIP-qPCR, dual-luciferase reporter assays, and molecular docking to determine downstream signaling and ezetimibe effects.

Main Results:

  • PRDM5 was identified as a pivotal ASCVD risk gene with significantly upregulated expression in patient monocytes and atherosclerotic plaques.
  • PRDM5 directly binds the ASK1 promoter, activating the ASK1/JNK/NF-κB signaling pathway.
  • This activation exacerbates macrophage lipid accumulation, inflammation, apoptosis, and endothelial dysfunction; ezetimibe was found to suppress PRDM5 transcriptional activity.

Conclusions:

  • PRDM5 acts as a common susceptibility gene for atherosclerotic cardiovascular disease (ASCVD).
  • PRDM5 facilitates pathogenic macrophage phenotypes through the ASK1/JNK/NF-κB cascade.
  • Ezetimibe demonstrates potential for therapeutic intervention by inhibiting PRDM5 activity.
Keywords:
ASK1AtherosclerosisEzetimibeMacrophagePRDM5

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