Fig. 5

NF-κB and NLRP3 signaling pathways in PH. a NF-κB signaling pathway and targeted therapy in PH. PDGF, hypoxia, MCT and cigarette smoke activate NF-κB in PASMCs and PAECs, promoting proliferation, resistance to apoptosis, and inflammation via p65 nuclear translocation, HIF-1α activation, and CaSR upregulation. In hypoxia-PH, NLRC3 and PGC-1α are reduced, leading to activation of p65 in PAECs, which drives apoptosis, migration, and EndMT. In IPAH, NF-κB is activated in macrophages, promoting inflammation. NF-κB inhibition can alleviate PH using agents like IMD-0354, Simvastatin, Atorvastatin, Ruscogenin, Prednisolone, ad-A20, BAY11-7082, Nicorandil, and TRE. IKK IκB kinase, IκB inhibitor of NF-κB, HIF-1α hypoxia-inducible factor 1-alpha, EV extracellular vesicle, HDAC10 histone deacetylase 10, CaSR calcium-sensing receptor, NLRC3 NLR family CARD domain-containing protein 3, PGC-1α peroxisome proliferator-activated receptor gamma coactivator-1 alpha, EndMT endothelial-to-mesenchymal transition, IPAH idiopathic pulmonary arterial hypertension, NF-κB nuclear factor kappa B, PASMC pulmonary artery smooth muscle cell, PAEC pulmonary artery endothelial cell, TRE triterpenoid, TGF-β transforming growth factor-β, VPO1 vascular peroxidase 1, PTPL1 protein tyrosine phosphatase L1, HOCl hypochlorous acid, MCT monocrotaline. b NLRP3 signaling pathway and targeted therapy in PH. Su/Hx-PAH activates NLRP3 in PAECs, causing proliferation, apoptosis resistance, and pyroptosis. In macrophages, this trigger activates NLRP3, promoting inflammation and IL-1β release. In IPAH and Su/Hx-PAH, NLRP3 is activated in PASMCs, inducing pyroptosis and proliferation. In MCT-PH, NLRP3 activation in monocytes and cardiomyocytes drives hypertrophy and mitochondrial dysfunction. NLRP3 activation contributes to PH progression. PNU-282987 and Astragaloside IV inhibit NLRP3 in macrophages and PAECs. PAEC pulmonary artery endothelial cell, ROS reactive oxygen species, NLRP3 NLR family pyrin domain containing 3, Su/Hx-PAH SU5416-hypoxia-induced pulmonary arterial hypertension, GPR146 G-protein coupled receptor 146, MCT monocrotaline, HMGB1 high-mobility group box 1, STING stimulator of interferon genes, IL-1β interleukin-1 beta, SOD2 superoxide dismutase 2, IPAH idiopathic pulmonary arterial hypertension, MCT-PH monocrotaline-induced pulmonary hypertension, PNU-282987 a selective α7-nicotinic acetylcholine receptor agonist, Astragaloside IV an active compound from Astragalus membranaceus