肺动脉高压（PH）是一种与肺动脉平滑肌细胞（PASMC）过度增殖相关的危及生命的综合征，其表现出与癌细胞相似的特征。目前，PH 没有治愈方法。 LKB1被称为抑癌基因，对癌细胞具有抗增殖作用。然而，其在PH发展中的作用和机制仍不清楚。采用功能获得和丧失策略来阐明LKB1调节PH发生和进展的机制。 Sugen5416/缺氧 (SuHx) PH 模型用于体内研究。我们不仅在 SuHx 小鼠模型的肺血管中观察到 LKB1 的表达下降，而且在暴露于缺氧的人肺动脉平滑肌细胞 (HPASMC) 中也观察到 LKB1 的表达下降。平滑肌特异性 LKB1 敲除显着加重 SuHx 诱导的小鼠 PH。 RNA测序分析显示，与对照组相比，LKB1SMKO小鼠主动脉中骨形态发生蛋白4（BMP4）显着增加，从而将BMP4确定为LKB1的新靶标。低氧条件下培养的 HPASMC 中 LKB1 敲低会增加 BMP4 蛋白水平以及 HPASMC 增殖和迁移。免疫共沉淀分析表明，LKB1 通过磷酸化直接调节 BMP4 蛋白降解。在治疗上，抑制 SMC 中的 BMP4 表达可减轻 LKB1SMKO 小鼠的 PH。我们的研究结果表明，LKB1 通过增强 BMP4 的溶酶体降解来减弱 PH，从而抑制 HPASMC 的增殖和迁移。调节 SMC 中的 LKB1-BMP4 轴可能是 PH 的一种有前途的治疗策略。

Pulmonary hypertension (PH) is a life-threatening syndrome associated with hyperproliferation of pulmonary artery smooth muscle cells (PASMCs), which exhibit similar features to cancer cells. Currently, there is no curative treatment for PH. LKB1 is known as a tumor suppressor gene with an anti-proliferative effect on cancer cells. However, its role and mechanism in the development of PH remain unclear. Gain-and loss-of-function strategies were used to elucidate the mechanisms of LKB1 in regulating the occurrence and progression of PH. Sugen5416/Hypoxia (SuHx) PH model was utilized for in vivo study. We observed not only a decreased expression of LKB1 in the lung vessels of the SuHx mouse model, but also in human pulmonary artery smooth muscle cells (HPASMCs) exposed to hypoxia. Smooth muscle-specific LKB1 knockout significantly aggravated SuHx-induced PH in mice. RNA sequencing analysis revealed a substantial increase in bone morphogenetic protein-4 (BMP4) in the aortas of LKB1SMKO mice compared with controls, identifying BMP4 as a novel target of LKB1. LKB1 knockdown in HPASMCs cultured under hypoxic conditions increased BMP4 protein level and HPASMC proliferation and migration. The co-immunoprecipitation analysis revealed that LKB1 directly modulates BMP4 protein degradation through phosphorylation. Therapeutically, suppressing BMP4 expression in SMCs alleviates PH in LKB1SMKO mice. Our findings demonstrate that LKB1 attenuates PH by enhancing the lysosomal degradation of BMP4, thus suppressing the proliferation and migration of HPASMCs. Modulating LKB1-BMP4 axis in SMC could be a promising therapeutic strategy of PH.