Lactate-driven histone lactylation by AARS1 promotes pulmonary arterial hypertension

Glycolytic reprogramming drives lactate accumulation in pulmonary arterial hypertension (PAH). We used a monocrotaline-induced rat PAH model and platelet-derived growth factor-BB (PDGF-BB)-stimulated pulmonary artery smooth muscle cells (PASMCs), together with oxamate intervention and molecular assays, to investigate lactate-mediated histone lactylation. PAH tissues exhibited increased lactate, MCT4, and histone H3 lysine 18 lactylation (H3K18la), accompanied by reduced HDAC1. Oxamate reversed these alterations and alleviated pulmonary vascular remodeling. Manipulating MCT4 expression modulated H3K18la levels. Upregulated alanyl-tRNA synthetase 1 (AARS1) displayed enhanced nuclear localization after lactate exposure; AARS1 depletion suppressed lactate-triggered H3K18la and PASMC proliferation. H3K18la was enriched at the Ctnnb1 promoter and correlated with enhanced Ctnnb1 transcription. These findings suggest that lactate may act as an epigenetic signal, linking glycolysis to Ctnnb1 activation through AARS1-associated H3K18la, thereby offering a potential target for PAH treatment.