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

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) has shared genetic susceptibility across various vascular lesions. Identification of common pathogenic factors for multi-territorial atherosclerosis is urgently required. We hypothesize that PR domain zinc finger protein 5 (PRDM5) acts as a shared pathogenic regulator to facilitate systemic atherosclerotic lesions by modulating monocyte-macrophage function. METHODS: Multi-trait genome-wide association studies (GWAS) datasets were analyzed via genomic structural equation modeling (Genomic SEM) to uncover shared risk loci underlying ASCVD. Transcriptome-wide association study (TWAS) was performed in CD14+ monocytes to prioritize candidate genes. PRDM5 expression was validated in clinical peripheral blood monocytes and atherosclerotic plaques. Cellular functional assays, chromatin Immunoprecipitation quantitative real-time PCR (ChIP-qPCR), dual-luciferase reporter assay and molecular docking were combined to decipher downstream signaling and ezetimibe-mediated therapeutic effects. RESULTS: PRDM5 was identified as a pivotal ASCVD risk gene, with significantly upregulated expression in monocytes and plaque tissues from patients. Mechanistically, PRDM5 directly binds the ASK1 promoter to trigger ASK1/JNK/NF-κB signaling, aggravating macrophage lipid overloading, inflammatory activation and apoptosis, and further inducing endothelial dysfunction through paracrine mediators. Ezetimibe suppresses the transcriptional activity of PRDM5. CONCLUSION: PRDM5 serves as a common susceptibility gene for ASCVD and facilitates macrophage pathogenic phenotypes via the ASK1/JNK/NF-κB cascade.