Challenges and opportunities in targeting epigenetic mechanisms for pulmonary arterial hypertension treatment

Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by elevated pulmonary vascular resistance and pulmonary artery pressure, resulting from a multitude of etiological factors. If left untreated, PAH progressively leads to right heart failure and is associated with high mortality. The etiology of PAH is multifactorial, encompassing both congenital genetic predispositions and acquired secondary influences. Epigenetics, which refers to the regulation of gene expression through chromosomal alterations that do not involve changes in the DNA sequence, has garnered significant attention in PAH research. This includes mechanisms such as DNA methylation, histone modification, and RNA modification. Aberrant epigenetic modifications have been closely linked to the dysregulated proliferation and apoptosis of pulmonary artery smooth muscle cells and endothelial cells, suggesting that these alterations may serve as pivotal drivers of the pathophysiological changes observed in PAH. This review examines the potential impact of epigenetic alterations on the pathogenesis of PAH, highlighting their promise as therapeutic targets. Furthermore, we explore emerging therapeutic strategies and compounds aimed at modulating these epigenetic markers, and discusses their potential applications in both preclinical models and clinical trials. As our understanding of epigenetics deepens, it holds the potential to unlock novel avenues for the precise, individualized treatment of PAH, offering a new frontier in the fight against this debilitating disease.