Epigenetic remodeling in pulmonary arterial hypertension: metabolic regulation and therapeutic opportunities

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy characterized by endothelial dysfunction, smooth muscle cell proliferation, vascular remodeling, and right ventricular pressure overload. Although contemporary therapies improve symptoms, hemodynamics, and clinical outcomes, they do not fully reverse the persistent pulmonary vascular cell phenotypes that sustain disease progression. Disease-associated vascular cell phenotypes can persist beyond the immediate signaling environment, indicating that mechanisms capable of stabilizing abnormal cell states contribute to PAH. These include regulatory reprogramming, sustained signaling, and the selection or expansion of abnormal cell populations. Epigenetic remodeling provides a framework for understanding this biology. DNA methylation, histone acetylation, histone methylation, chromatin accessibility, and acetyl-lysine reader pathways have all been implicated in PAH pathogenesis. PAH is characterized by profound metabolic reprogramming, including aerobic glycolysis, impaired mitochondrial oxidative metabolism, altered redox homeostasis, glutamine dependence, and changes in lipid and acetyl-CoA metabolism. These two fields should not be considered separately. Many metabolites disrupted in PAH directly regulate chromatin-modifying enzymes. Acetyl-CoA fuels histone acetylation, NAD+ controls sirtuin-dependent deacetylation, S-adenosylmethionine supports DNA and histone methylation, and α-ketoglutarate and oxygen are required for dioxygenases that mediate DNA and histone demethylation, respectively. Lactate is also emerging as a candidate interface between glycolytic remodeling and chromatin regulation through histone lactylation, and RNA N6-methyladenosine constitutes a parallel epitranscriptomic layer governed by the same pool of metabolites. This review focuses on PAH, with an emphasis on pulmonary artery endothelial and smooth muscle vascular cells. We first define the pulmonary vascular and transcriptional context in which persistent disease phenotypes develop and set out the evidence required to distinguish metabolic-epigenetic coupling from durable cellular memory. We summarize the core epigenetic mechanisms relevant to PAH and discuss the specific epigenetic abnormalities reported in pulmonary vascular cells. Finally, we examine how metabolic dysfunction shapes the epigenetic landscape, consider the therapeutic implications, and outline the priorities needed to move the field toward translational precision.