Abstract

Lactate produced during glycolysis plays a critical role in pulmonary arterial hypertension (PAH) by mediating protein lactylation and other molecular effects. Targeting lactylation-related signaling holds significant promise for the treatment of PAH. Therefore, we aimed to investigate lactylation-associated gene signatures and identify the critical role of hub genes. Transcriptomics analysis and mendelian randomization (MR) were applied to screen hub lactylation-related genes. 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) was identified as a hub lactylation-related gene. HIBCH was significantly upregulated in platelet-derived growth factor (PDGF) stimulated pulmonary arterial smooth muscle cells (PASMCs) and lung tissues in PAH. MR analysis revealed that HIBCH upregulation correlated with higher PAH risk. Subsequently, the cell viability, proliferation and migration were detected to elucidate the effects of HIBCH on PASMCs. HIBCH knockdown markedly reduced the PDGF–induced lactate production, proliferation and migration in PASMCs. Further, cyproheptadine was screened as a potential HIBCH inhibitor. Cyproheptadine suppressed PASMCs proliferation and alleviated the monocrataline-induced pulmonary hypertension in vivo. Together, we identified the lactylation-related gene HIBCH as a risk factor for PAH and provided a novel therapeutic candidate for the treatment of PAH.