YAP-mediated glycolysis promotes pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension

作者：Wenhua Shi, Liping Chen, Wei Zhang, Ping He, Yonghong Zhang, Kecheng Yan, Cong Li, Ning Pu, Yuan Liu, Shuzhen Ma, Rui Ke · 发表于：Journal of Biological Chemistry · 年份：2025 · DOI：10.1016/j.jbc.2025.110836 · 被引用次数：6 · 研究领域：Pulmonary Hypertension Research and Treatments、Lipid metabolism and biosynthesis、Heat shock proteins research

Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) has been identified as a key enzyme regulating glycolysis. However, the molecular mechanisms underlying PFKFB3 regulation and glycolysis reprogramming in PAH remain unclear. Here, primary cultured pulmonary arterial smooth muscle cells (PASMCs) and monocrotaline-induced PAH rats were used to investigate these unknown mechanisms. We found that PFKFB3 expression and PASMC glycolysis were significantly increased in high mobility group box 1 (HMGB1)-treated cells, accompanied by the dephosphorylation and nuclear translocation of Yes-associated protein (YAP) via Rho-associated protein kinase signaling. Activation of YAP then acted as a transcriptional coactivator in conjunction with transcriptional enhancer activator domain 1, bolstering the transcription of the crucial glycolytic enzyme PFKFB3, consequently amplifying PASMC glycolysis. Rho-associated protein kinase inhibition, YAP or PFKFB3 knockdown, or glycolysis blockage diminished HMGB1-induced PASMC proliferation. In rats with monocrotaline-induced PAH, interventions such as inhibiting HMGB1 with glycyrrhizin, suppressing YAP activation with verteporfin, and targeting PFKFB3 with 3-PO effectively halted PAH progression. Our findings suggest that targeting the HMGB1-YAP-PFKFB3-glycolytic pathway is a promising strategy for preventing and treating PAH.