Multi-omics interrogation of energy metabolism reveals novel causal targets in pulmonary arterial hypertension

Background Pulmonary arterial hypertension (PAH) is a highly lethal rare cardiopulmonary disease characterized by pulmonary vascular remodeling and elevated vascular resistance. Existing treatments offer limited efficacy, highlighting an urgent need for novel therapeutic targets. Energy metabolism-related genes (EMRGs) have been implicated in cardiopulmonary diseases, yet their causal role in PAH remains unclear. Purpose This study aims to systematically investigate the causal relationships between energy metabolism-related proteins and PAH using multi-omics data and rigorous genetic epidemiology methods, thereby identifying potential therapeutic targets. Methods We integrated pQTL data from three large-scale cohorts (deCODE olink/soma and UKB-PPP) with two PAH genome-wide association studies (GCST007228 and finn-b-I9_HYPTENSPUL). Two-sample Mendelian randomization (MR), summary-data-based MR (SMR), colocalization, and phenome-wide association analysis (PheWAS) were performed. Findings were validated using differential expression analysis in combined GEO datasets and functional enrichment analysis. Results MR analysis identified multiple energy metabolism-related proteins with significant causal effects on PAH. Notably, EDN1, IGFBP1, IGFBP3, PCSK9, PFKM, and CAT emerged as key proteins with consistent causal evidence across multiple cohorts and outcomes. SMR and colocalization analyses further supported these findings, with PCSK9 demonstrating the highest probability of shared causal variants (Top.SNP.PP.H4=1). Sensitivity analyses confirmed the robustness and directionality of these causal relationships, with no significant heterogeneity or horizontal pleiotropy detected. PheWAS indicated that most key proteins lack significant associations with other clinical phenotypes, suggesting favorable safety profiles for therapeutic targeting. Differential expression analysis in lung tissues from PAH patients validated the dysregulation of these proteins (EDN1, PFKM, CAT), and functional enrichment highlighted pathways related to peptide hormone response, insulin-like growth factor signaling, and HIF-1 signaling. Conclusion This study establishes robust genetic causal evidence linking six energy metabolism-related proteins (EDN1, IGFBP1, IGFBP3, PCSK9, PFKM, CAT) to PAH. These findings provide promising therapeutic targets and a molecular foundation for advancing precision medicine in PAH.