Jun-Zhuo Shi, Jing-Song Ye, Xiao-Rui An, Guo Cheng, Xin Fan, Fang-Fang Meng, Ou Yang, Yang-Han-Yue Zhou, Meng-Jie Zhang, Tian-Yi Yuan, Yi Yan, Yang-Yang He
Huaihe Hospital and Henan University. Shanghai Children’s Medical Center and Shanghai Jiao Tong University School of Medicine. Chinese Academy of Medical Sciences and Peking Union Medical College.
Pharmacology and Therapeutics
Pharmacol Ther 2026;
DOI: 10.1016/j.pharmthera.2026.109085
Abstract
Pulmonary arterial hypertension (PAH) is a severe, progressive hemodynamic disorder characterized by pathological pulmonary vascular remodeling and right ventricular dysfunction, in which metabolic reprogramming is recognized as a pivotal pathogenic mechanism driving disease progression. This review synthesizes the metabolic pathways, key regulatory targets, and therapeutic implications underlying PAH pathogenesis, focusing on the major cell types involved in its pathogenesis: dysfunctional pulmonary arterial endothelial cells (PAECs), abnormally proliferating pulmonary arterial smooth muscle cells (PASMCs), activated pulmonary artery adventitial fibroblasts (PAAFs), infiltrating immune cells, and right ventricular cardiomyocytes (RVCMs) that undergo compensatory remodeling to counteract increased pressure overload. The primary highlight is its cell-specific analytical framework, which systematically delineates shared metabolic hallmarks and distinct cell-type-specific mechanisms. Shared metabolic features across these cell populations include enhanced aerobic glycolysis, impaired mitochondrial oxidative phosphorylation, and dysregulated amino acid metabolism. Cell-specific mechanisms encompass dysfunction of PAECs, phenotypic switching of PASMCs, PAAFs-mediated adventitial fibrosis, metabolic inflexibility of RVCMs, and inflammatory polarization of immune cells. By integrating these multifaceted findings, the review provides critical insights into the metabolic underpinnings of PAH, emphasizing cell-specific metabolic regulation as a strategy for targeted therapy to reverse vascular remodeling, mitigate right ventricular dysfunction, and improve clinical outcomes.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Review Articles Concerning Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: No