Objective:To investigate whether secreted modular calcium-binding protein 2(SMOC2) participates in miR-125a/miR-150-mediated phenotypic switching of pulmonary artery smooth muscle cell (PASMC) in pulmonary hypertnesion (PH). Methods:Human lung tissues and lung sections were collected from pulmonary hypertension(PH) patients and healthy controls. PH animal models were established in mice exposed to chronic hypoxia and in rats treated with SU5416 combined with chronic hypoxia. SMOC2 expression levels in lung tissues from PH patients, mice, and rats were assessed by Western blot, while its cellular localization was determined by immunofluorescence staining. Human PASMC were transfected with SMOC2 siRNA and miRNA mimics, or treated with recombinant SMOC2 protein. PASMC proliferation and migration were evaluated using EdU incorporation and wound healing assays. Dual-luciferase reporter assays was performed to validate SMOC2 as a direct target of miR-125a/miR-150. Results:SMOC2 expression was significantly upregulated in the lung tissues fromhuman and animal PH samples, thus in hypoxic PASMC. Inhibition of SMOC2 attenuated proliferation, migration, and phenotype switching in PASMC, whereas treatment with recombinant SMOC2 protein promoted PASMC proliferation and migration. miR-125a and miR-150 recognized and inhibted SMOC2 mRNA translation in PASMC. miR-125a and miR-150 mimics inhibited hypoxia-induced proliferation and phenotype switch of PASMC. Conclusion:miR-125a/miR-150 regulate hypoxia-induced PASMC phenotypic switching by directly targeting SMOC2, providing a potential therapeutic target for PH treatment.