Integrated multi-omics and machine learning identify core mechanobiology-associated immune genes in pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) involves vascular remodeling and altered mechanical signaling. The immune-associated transcriptomic changes accompanying this environment remain incompletely characterized. Methods: We integrated bulk lung (GSE15197), PBMC (GSE33463), and single-cell RNA-seq (GSE169471) data using a curated set of 2, 537 mechanical-related genes. WGCNA, LASSO, random forest, and single-cell localization supported candidate prioritization. The four-gene panel was examined in a monocrotaline-induced PH rat model and PBMCs from 10 IPAH patients and 10 controls. Results: PAH transcriptomes showed enrichment of stress-fiber, actomyosin, ECM, and immune-related programs. CD83, CD86, IL6, and TLR7 were prioritized, with compartment-dependent expression patterns. Single-cell data localized CD83/CD86 to myeloid/APC compartments and IL6 to endothelial/fibroblast populations; TLR7 was sparsely detected. In MCT-treated rat lungs, CD86 and TLR7 proteins increased, whereas CD83 and IL-6 decreased. Clinical PBMCs showed corresponding expression directions, and each gene had an AUC >0.7. The exploratory four-gene disease-state score achieved an internal cross-validated AUC of 0.765. Conclusions: The four candidates provide a cellular and molecular context for investigating immune-stromal interactions in PAH, including responses to noninfectious vascular injury. The panel showed moderate internal discrimination. These findings support further clinical and functional investigation but do not establish direct mechanotransduction targets or a causal pathway linking mechanical stress to vascular inflammation.