Lactylation modification: a new bridge connecting macrophage metabolism and pulmonary hypertension

Abstract Pulmonary hypertension (PH) is a multifactorial, progressive disease characterized by pulmonary vascular remodeling and right heart failure, representing a substantial global health burden. Dysregulated interactions among multiple cell types within the pulmonary vascular microenvironment, particularly macrophage polarization imbalance with a predominant transition toward the M2 phenotype, play a critical role in driving pro-fibrotic and pro-remodeling processes in PH. Lactylation, a novel post-translational modification that covalently links lactate to lysine residues, translates glycolytic metabolic signals into persistent epigenetic changes. Recent advances have identified lactylation on histones (e.g., H3K18la), non-histone proteins, and mitochondrial proteins, revealing new layers of regulatory complexity. Elucidating the role of lactylation, particularly its impact on macrophage polarization and vascular cell function, may offer novel insights into the pathogenesis of PH and identify potential therapeutic targets. Key points • Macrophage polarization imbalance (predominant M2 phenotype) is a critical driver of pulmonary vascular remodeling in pulmonary hypertension (PH), and lactylation serves as a novel metabolic–epigenetic bridge linking macrophage metabolic reprogramming and phenotypic switching. • Lactylation modifications occur extensively on histones, non-histone proteins, and mitochondrial proteins in PH, regulating fibrosis-related pathways, arginine metabolism signaling, and the dysfunction of pulmonary vascular cells. • Targeting lactylation and lactate metabolism represents a promising therapeutic strategy for PH, supported by our previous studies on M2 macrophage polarization and ongoing lactylomic research.