Work

Sotatercept in Pulmonary Arterial Hypertension: Molecular Mechanisms, Clinical Evidence, and Emerging Role in Reverse Remodelling

Year: 2026

Type: article

Abstract: Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials-PULSAR, STELLAR, ZENITH, and HYPERION-demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept's therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27020767

Authors: Ioan Tilea, Dragos-Gabriel Iancu, Ovidiu Fira-Mladinescu, Nicoleta Bertici, Andreea Varga

Institutions: Universitatea de Medicină, Farmacie, Științe și Tehnologie „George Emil Palade” din Târgu Mureș, Spitalul Clinic Judetean de Urgenta Târgu Mureş, Victor Babeș University of Medicine and Pharmacy Timișoara, Spitalul Clinic Dr. Victor Babes

Language: English

Topic: Pulmonary Hypertension Research and Treatments

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499