Multi-omic analysis of human PHACTR1 signaling networks.

Genetic studies have linked PHACTR1 to a range of vascular diseases, underscoring its pivotal role in vascular biology. However, the full spectrum of PHACTR1-mediated signaling pathways remains largely unexplored. To bridge this gap, we employ a multi-omics pipeline combining pairwise differential expression analysis, multi-omics pathway integration, and feature-level correlation analyses across four distinct omics datasets to map the global signaling networks driven by PHACTR1. By integrating transcriptomic, proteomic, metabolic, and lipidomic profiles from human HT1080 cells with PHACTR1 overexpression or knockdown, and then validating key findings in primary human endothelial cells, here we show that PHACTR1 exerts broad control over fundamental cellular processes beyond cytoskeletal regulation. We demonstrate that PHACTR1 governs cell cycle progression, validating that increased expression alters key regulatory proteins. We also uncover a distinct function in iron metabolism, showing PHACTR1 regulates essential cellular iron-storage proteins and identify the PHACTR1 protein within the mitochondria where it directs morphology and bioenergetics through a signaling axis involving AKAP1 and Drp1. These mitochondrial changes align with observed shifts in lipid metabolism and correlations in human arterial tissue. These findings provide a systems-level blueprint of PHACTR1 function, revealing how this gene influences vascular health and offering potential targets for therapeutic intervention.