Mechanism of action of first-in-class drugs. (A) In pulmonary arterial hypertension (PAH), endothelin-1 (ET-1) activates ET_A and ET_B receptors leading to endothelial dysfunction, vasoconstriction, vascular remodelling (hypertrophy, fibrosis, and proliferation), inflammation, sympathetic activation, and increased aldosterone synthesis. Aprocitentan, the active metabolite of macitentan, prevents the binding of ET-1 to both ET_A/ET_B receptors and inhibits ET-1-mediated signalling. (B) The fixed-dose combination of macitentan, a dual ET_A and ET_B receptor antagonist, and sildenafil, a phosphodiesterase-5 inhibitor (PDEI), simultaneously targeted the ET-1 and the nitric oxide (NO) pathways involved in the pathophysiology of PAH. NO produced in endothelial cells (ECs) enter the pulmonary vascular smooth muscle cells (PVSMCs) binds to soluble guanylate cyclase (sGC) increasing its catalytic activity, and the conversion of guanosine-5′-triphosphate (GTP) into guanosine 3′,5′-cyclic monophosphate (cGMP), which causes smooth muscle relaxation and antiproliferative effects. This signalling pathway is counterbalanced by sildenafil, which blocks the degradation of cGMP to 5′-guanosine monophosphate. The simultaneous blockade of the ET-1 and NO signalling with macitentan and sildenafil allows to reach better outcomes in patients with PAH as compared with each drug in monotherapy. (C) Sotatercept rebalances growth-promoting and growth-inhibiting signalling. In PAH there is a down-regulation of the bone morphogenetic protein (BMP) receptor type II (BMPR2)–Smad1/5/8 pathway in PVSMCs leading to an increased production of activin ligands and an up-regulation of the activin receptor type IIA (ActRIIA)–Smad2/3 pathway. Increased phosphorylated Smad (pSmad)2/3 activity promotes the expression of endogenous BMP antagonists, gremlin-1 and noggin, which further reduces BMP–Smad1/5/8 signalling. The result is a reduction in antiproliferative and an increase in proproliferative signalling pathways counteracting pulmonary vascular remodelling. Sotatercept acts to sequester excess of ActRIIA ligands, thereby reducing ActRIIA–Smad2/3 signalling to rebalance growth-promoting and growth-inhibiting signalling. ALK, activin receptor-like kinase; pSmad, phosphorylated Smad; Smad, small mothers against decapentaplegic protein.