Comprehensive profiling of lactylation-associated genes in pulmonary hypertension through bulk and single-cell RNA sequencing integration

BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder with high pulmonary arterial pressure, causing right ventricular dysfunction. Understanding PH's molecular basis is vital for therapy development, but research on lactylation's role in PH is limited and needs more investigation. METHODS: We integrated bulk RNA-seq datasets (GSE113439, GSE186996) and single-cell RNA-seq data (GSE210248) from PH patients and controls Differential expression analysis identified lactylation-associated hub genes. Functional enrichment (GO/KEGG), immune infiltration, and cell-cell communication analyses were performed. In vitro validation included RT-PCR and western blot on hypoxic pulmonary artery smooth muscle cells (PASMCs). RESULTS: We identified lymphocyte cytosolic protein 1 (LCP1) as a core lactylation-related hub gene, significantly upregulated in PH and validated in human/rat models. Single-cell profiling revealed elevated lactylation levels in vascular smooth muscle cells (VSMCs), T lymphocytes, and monocytes/macrophages within PH tissues. Cell communication analysis implicated TWEAK signaling from monocytes/macrophages to VSMCs as a driver of vascular remodeling. Metabolic pathways (e.g., glycolysis, bile acid metabolism) correlated strongly with lactylation activity. In vitro, hypoxia-induced LCP1 overexpression in PASMCs confirmed bioinformatic findings. CONCLUSION: We analyzed lactylation-related genes in PH, identifying LCP1 as a key diagnostic marker, and described immune cell lactylation in PH patients, offering insights for future research.