Autophagy-Targeted Vascular Remodeling in Pulmonary Arterial Hypertension: Molecular Mechanisms and Therapeutic Perspectives

Abstract

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by progressively increased pulmonary vascular resistance and right heart failure. Its pathogenesis involves multiple factors, including genetic predisposition, inflammation, oxidative stress, and imbalances between cell proliferation and apoptosis. Recent studies indicate that autophagy has a context-dependent dual role in PAH. Flux-competent autophagy may be protective by clearing damaged mitochondria, limiting excessive inflammation, and maintaining metabolic homeostasis, whereas excessive autophagy initiation or impaired autophagosome-lysosome degradation may promote metabolic dysfunction, inflammatory signaling, abnormal vascular cell phenotypes, and pulmonary vascular remodeling. This focused narrative review summarizes the molecular mechanisms and key signaling pathways linking autophagy to PAH, with emphasis on PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) energy-sensing axis. It also evaluates potential therapeutic strategies targeting key nodes of autophagy, such as AMPK activators and mTOR inhibitors, along with their clinical research progress. Finally, this review provides an outlook on future research directions, emphasizing the need to further elucidate the dynamic regulatory mechanisms and cell-type specificity of autophagy in order to advance the clinical translation of autophagy-targeted precision therapies for PAH.