Sotatercept and its rodent analog, RAP-011, are ActRIIA-Fc fusion proteins that neutralize activin-class ligands (activins A/B, GDF8, GDF11) elevated in PAH.73,397 By modulating Smad2/3 signaling, they exert anti-proliferative, pro-apoptotic, and anti-inflammation effects in cellular and animal PAH models.73,397,398 In MCT-PAH and Su/Hx-PAH rat models, it reduces mPAP and pulmonary arterial remodeling without impacting systemic arterial pressure89 (Table 1). This evidence concerns the gene SMAD2 and pulmonary arterial hypertension.