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PAH pathogenesis is strongly associated with mutations of the Transforming Growth Factor Beta (TGF\u2010\u03b2) superfamily signaling pathway, which has previously been challenging to target therapeutically. Sotatercept, a fusion protein of the extracellular portion of the activin type 2 receptor A (ACVR2A) and the human IgG1 Fc domain, is the first activin signaling inhibitor (ASI) FDA\u2010approved for the treatment of PAH, demonstrating efficacy across the risk spectrum in PAH. This soluble protein binds to a range of circulating TGF\u2010\u03b2 superfamily ligands, including activins A and B, growth and differentiation factors (GDFs) 8 and 11, as well as some bone morphogenetic proteins (BMPs). Other ASIs have been developed primarily for hematologic indications, such as anemias and cytopenias associated with \u03b2\u2010thalassemia, myelodysplastic syndromes, and myelodysplastic neoplasms. 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In this state\u2010of\u2010the\u2010art review, we brought together basic and clinical researchers, and industry scientists under the umbrella of the Pulmonary Vascular Research Institute (PVRI) Innovative Drug Discovery Initiative (IDDI) to discuss the biology of ASIs, the importance of specific BMP ligands, efficacy and side effect profiles, and considerations in the development of next\u2010generation ASIs.<\/jats:p>","DOI":"10.1002\/pul2.70353","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T09:46:44Z","timestamp":1784022404000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Activin Signaling Inhibitors in Pulmonary Hypertension: A State\u2010of\u2010the\u2010Art Review"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3443-5040","authenticated-orcid":false,"given":"Sudarshan","family":"Rajagopal","sequence":"first","affiliation":[{"name":"Department of Medicine Duke University School of Medicine Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Abueg","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc. 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