Integrated bioinformatics identifies ferroptosis biomarkers and therapeutic targets in idiopathic pulmonary arterial hypertension

Abstract

Abstract Idiopathic pulmonary arterial hypertension (IPAH), a rare and devastating pulmonary vascular disorder, is characterized by cellular proliferation and vascular remodeling. Although previous studies have underscored that ferroptosis, an iron-dependent cell death process, plays an important regulatory role in pulmonary artery hypertension, its role remains understudied. Gene expression profiles were downloaded from the Gene Expression Omnibus(GEO). Differentially expressed genes (DEGs) were screened using R software and intersected with a ferroptosis database (FerrDb V1) to identify ferroptosis-related DEGs. GO and KEGG analyses were performed to explore biological functions and potential pathways. LASSO and SVM-RFE algorithms were used to identify optimal gene biomarkers for IPAH. GSVA and GSEA were conducted to explore biological functions and potential pathways associated with these biomarkers. The CIBESORT software was employed to predict immune genes and functions. Of 237 ferroptosis-related genes (FRGs), 27 differentially expressed FRGs (DE-FRGs) showed significant differences between IPAH and normal samples in GSE48149, with 15 downregulated and 12 upregulated genes. Six DE-FRGs, including KEAP1, TNFAIP3, MEG3, NFS1, PRDX1, and BEX1, were identified as predictive diagnostic genes for IPAH. Among these DE-FRGs, PRDX1 and TNFAIP3 were the most promising diagnostic genes for IPAH and may play a corresponding role in IPAH by participating in the cell cycle, lysosomes, immune response, vascular smooth muscle contraction, and various diseases. CIBERSORT analysis revealed a positive correlation between neutrophils and TNFAIP3, whereas macrophages M0 exhibited a negative correlation with PRDX1. Through comprehensive bioinformatics analysis, we identified six differentially expressed ferroptosis-related genes (DE-FRGs)—KEAP1, TNFAIP3, MEG3, NFS1, PRDX1, and BEX1—in idiopathic pulmonary arterial hypertension (IPAH). Among these, PRDX1 and TNFAIP3, which play key roles in IPAH pathogenesis, emerged as the most promising diagnostic biomarkers.