Integrative Analysis of Endothelial Cell Senescence‐Related Genes in Idiopathic Pulmonary Fibrosis

ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which endothelial cell senescence (ECS) plays a key role. By integrating two GEO transcriptome datasets (145 IPF patients and 84 controls) and applying LASSO, SVM‐RFE, and Boruta algorithms, four key ECS‐related genes (ECSRGs), MYCT1, PLEKHA1, PCDH12, and PLXND1, were identified. MYCT1 and PLEKHA1 were downregulated by about 26% and 75%, while PCDH12 and PLXND1 were upregulated by 2.4‐ and 1.9‐fold ( p < 0.0001). The four‐gene nomogram achieved 93.6% diagnostic accuracy. In TGF‐β1–induced HUVECs, silencing MYCT1 or PLEKHA1 increased senescent cells by ~1.4‐fold, whereas silencing PCDH12 or PLXND1 reduced α‐SMA and COL1A1 levels by ~40%. In bleomycin‐induced mice, valproic acid (VPA) lowered collagen deposition by ~60% and normalized gene expression. MYCT1 and PLEKHA1 act as anti‐senescence factors, while PCDH12 and PLXND1 act as pro‐fibrotic drivers. The four‐gene model shows strong diagnostic potential, and VPA may serve as a therapeutic candidate targeting ECS in IPF.