Objective: This study aims 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 SU-5416 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 miRNA mimics and SMOC2 siRNA, or treated with recombinant SMOC2 protein. PASMC proliferation and migration were evaluated using EdU incorporation and wound healing assays, along with Western blot analysis. 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 from PH patients, mice, and rats, as well as in hypoxia-induced PASMC. Knockdown of SMOC2 significantly inhibited hypoxia-induced PASMC proliferation and migration, whereas recombinant SMOC2 protein treated exacerbated these effects. Dual-luciferase reporter assays confirmed that SMOC2 is a direct target of miR-125a/miR-150. miR-125a or miR-150 mimics led to a reduction in SMOC2 protein levels in PASMC. Rescue experiments demonstrated that recombinant SMOC2 protein partially reversed the inhibitory effect of miR-125a/miR-150 overexpression on PASMC proliferation and migration. Conclusion: miR-125a/miR-150 regulate hypoxia-induced PASMC phenotypic switching by directly targeting SMOC2, providing a potential therapeutic target for PH treatment