{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:34:26Z","timestamp":1791646466797,"version":"4.3.4"},"reference-count":121,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Romania","award":["511\/7\/17 January 2022"],"award-info":[{"award-number":["511\/7\/17 January 2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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-\u03b2 (TGF-\u03b2) 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\u2014PULSAR, STELLAR, ZENITH, and HYPERION\u2014demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms27020767","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:17:32Z","timestamp":1768292252000},"page":"767","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sotatercept in Pulmonary Arterial Hypertension: Molecular Mechanisms, Clinical Evidence, and Emerging Role in Reverse Remodelling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3828-1499","authenticated-orcid":false,"given":"Ioan","family":"Tilea","sequence":"first","affiliation":[{"name":"Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 38 Dr. Gh. Marinescu St., 540142 Targu Mures, Romania"},{"name":"Pulmonary Hypertension Centre, Department of Internal Medicine II\u2014Cardiology, County Emergency Hospital of Targu Mures, 50 Dr. Gh. Marinescu St., 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5372-6227","authenticated-orcid":false,"given":"Dragos-Gabriel","family":"Iancu","sequence":"additional","affiliation":[{"name":"Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9034-5218","authenticated-orcid":false,"given":"Ovidiu","family":"Fira-Mladinescu","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Personalised Medicine of Respiratory Diseases, Pulmonology University Clinic, Victor Babes University of Medicine and Pharmacy Timisoara, 2 Eftimie Murgu Square, 300041 Timisoara, Romania"},{"name":"Pulmonary Hypertension Treatment Unit, Centre of Expertise for Adult Rare Respiratory Diseases, Clinical Hospital of Infectious Diseases and Pneumophysiology \u201cDr. Victor Babes\u201d Timisoara, 13 Gheorghe Adam St., 300310 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9391-0200","authenticated-orcid":false,"given":"Nicoleta","family":"Bertici","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Personalised Medicine of Respiratory Diseases, Pulmonology University Clinic, Victor Babes University of Medicine and Pharmacy Timisoara, 2 Eftimie Murgu Square, 300041 Timisoara, Romania"},{"name":"Pulmonary Hypertension Treatment Unit, Centre of Expertise for Adult Rare Respiratory Diseases, Clinical Hospital of Infectious Diseases and Pneumophysiology \u201cDr. Victor Babes\u201d Timisoara, 13 Gheorghe Adam St., 300310 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6395-9476","authenticated-orcid":false,"given":"Andreea","family":"Varga","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Centre, Department of Internal Medicine II\u2014Cardiology, County Emergency Hospital of Targu Mures, 50 Dr. Gh. Marinescu St., 540136 Targu Mures, Romania"},{"name":"Faculty of Medicine in English, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 38 Dr. Gh. Marinescu St., 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.1093\/eurheartj\/ehx257","article-title":"A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension","volume":"39","author":"Kylhammar","year":"2018","journal-title":"Eur. 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