Association of Xeroderma Pigmentosum group F (XPF) with epigenetic regulation of T helper cell differentiation in coronary artery disease-associated prostate cancer

Background Coronary artery disease (CAD) and prostate cancer share common genetic and epigenetic risk factors. Xeroderma Pigmentosum group F (XPF), a DNA repair endonuclease, has been implicated in genomic stability and epigenetic regulation. This study investigated the association between XPF expression and epigenetic changes during T helper (TH) cell differentiation in CAD-associated prostate cancer (CAD-PC).Research design and methods CD4+ T cells isolated from healthy controls and CAD-PC patients were subjected to CRISPR/Cas9-mediated XPF knockout or overexpression. TH cell differentiation, chromatin enrichment, global m6A RNA methylation, DNA methylation, R-loop formation, and tumor cell cytotoxicity were evaluated using molecular and functional assays.Results XPF overexpression was associated with increased TH1 differentiation and elevated expression of XPF and TP53, whereas TH2, TH17, and Treg-associated markers were reduced. Increased enrichment of XPF and H3K4me3, together with reduced HDAC1, γH2A.X, and H3K27me3 enrichment, was observed at the TBX21 and IFNG loci. XPF overexpression was also associated with increased global m6A RNA methylation, reduced DNA methylation at TH1-associated loci, decreased R-loop accumulation, and enhanced tumor cell cytotoxicity in vitro.Conclusion These findings suggest that XPF expression is associated with a TH1-skewed epigenetic and immune profile in CAD-PC. However, the absence of disease-specific comparison groups and in vivo validation limits mechanistic interpretation, and further studies are required to establish causality. The present findings demonstrate an association between XPF and the observed TH1-associated epigenetic changes.