Fig. 4

MAPK and PI3K/Akt signaling pathways in PH. a MAPK signaling pathway and targeted therapy in PH. MAPK pathway is activated by cytokines and other stimuli, leading to the upregulation of cell cycle proteins and subsequently promoting proliferation. The ERK pathway inhibits cell apoptosis, while the p38 pathway promotes cell apoptosis. Activated p38 signaling contributes to mitochondrial dysfunction and also affects inflammation by inducing the secretion of inflammatory factors. ASK1 activates p38 and JNK, thereby stimulating PAF activation, migration, and proliferation. Paeoniflorin, and 3PO alleviate PH by inhibiting ERK and its related pathways, paeoniflorin by inhibiting p38 and its related pathways, and GS-444217 alleviate PH by inhibiting ASK1/JNK/p38 axis. PASMC pulmonary artery smooth muscle cell, PAEC pulmonary artery endothelial cell, PAF pulmonary artery fibroblast, Δψm mitochondrial membrane potential, ERK extracellular signal-regulated kinase, JNK c-Jun N terminal kinase, PPARγ peroxisome proliferator-activated receptor γ, PFKFB3 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, PDGF platelet-derived growth factor, ET-1 endothelin-1, PCNA proliferating cell nuclear antigen, 5-HT 5-hydroxytryptamine, EETs epoxyeicosatrienoic acids, Ano1 Anoctamin-1, NPR-C atrial natriuretic peptide clearance receptor, VEGF vascular endothelial growth factor, FGF2 fibroblast growth factor 2, ASK1 apoptosis signal-regulating kinase 1, ROS reactive oxygen species, MK2 mitogen-activated protein kinase -activated protein kinase 2, Elk-1 ETS-like transcription factor, IL interleukin, Egr-1 early growth response protein 1, Bcl-2 B-cell lymphoma 2, Bax Bcl-2 associated X, MSK1 mitogen and stress-activated kinase 1, DUSP1 dual specificity phosphatase-1, SphK1 sphingosine kinase 1, Caspase cysteinyl aspartate specific proteinase, miR microRNA, 3PO 3-(4-(trifluoromethyl phenyl)-1H-pyrazole. b PI3K/Akt signaling pathway and targeted therapy in PH. CTRP9 downregulation reduces PI3K/Akt in PAECs, causing apoptosis, inflammation (ET-1, MMP-2), and dysfunction. In late PH, miR-371b-5p/PTEN downregulation activates PI3K/Akt, promoting proliferation and oxidative stress (eNOS/NO) in PAECs. BMP4-induced activation of BMPR2/PI3K/Akt in PASMCs activates PI3K/Akt in PASMCs. PI3K/Akt activation in PH drives inflammation (NF-κB) and proliferation (Smad1/5/8, FOXO3a, Cyclin A) in PAECs and PASMCs. Inhibitors like Nobiletin and Resveratrol mitigate PH, while agent like Genistein counteract early PH. PI3K phosphoinositide 3-kinase, Akt protein kinase B, CTRP9 C1q/TNF-related protein 9, eNOS endothelial nitric oxide synthase, MMP-2 matrix metalloproteinase-2, BMP4 bone morphogenetic protein 4, BMPR2 bone morphogenetic protein receptor type 2, PTEN phosphatase and tensin homolog, NF-κB nuclear factor kappa B, ECM extracellular matrix, MCT monocrotaline, IPAH idiopathic pulmonary arterial hypertension, CircDiaph3 circular RNA diaphanous-related formin 3, IGFIR insulin-like growth factor 1 receptor, miR microRNA