Therapeutic targets for pulmonary arterial hypertension: insights into the emerging landscape

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease driven by vascular remodeling, right ventricular (RV) dysfunction, and metabolic and inflammatory dysregulation. Current therapies primarily target vasodilation to relieve symptoms but do not reverse disease progression. The recent approval of sotatercept, which modulates BMP/TGF-β signaling, marks a shift toward anti-remodeling therapies. Building on this, recent preclinical advances have identified promising therapeutic targets and potentially disease-modifying treatments. This review synthesizes the evolving preclinical landscape of emerging PAH therapeutic targets and drugs, highlighting innovative approaches aimed at addressing the underlying mechanisms of disease progression. Additionally, we discuss novel therapeutic strategies under development. Recent advances in PAH research have identified novel therapeutic targets beyond vasodilators, including modulation of BMP/TGF-β signaling, metabolic programs, epigenetics, cancer-related signaling, the extracellular matrix, and immune pathways, among others. Sotatercept represents a significant advance in therapies that go beyond vasodilation, and long-term safety, efficacy, and durability are being assessed. Future treatment strategies will focus on precision approaches, noninvasive technologies, and regenerative biology to improve outcomes and reverse vascular remodeling.