BACKGROUND: Adenomyosis is a common gynecological disorder characterized by the invasion of endometrial tissue into the myometrium, resulting in severe dysmenorrhea and menorrhagia. This study aimed to explore the role of SMOC2 (SPARC related modular calcium binding 2), an extracellular matrix (ECM) -associated protein, in the pathogenesis of adenomyosis and its potential as a therapeutic target. METHODS: We conducted a clinical study involving 35 patients diagnosed with adenomyosis and 30 controls. Ectopic endometrial tissue samples were collected and analyzed using immunohistochemistry (IHC), Masson staining, and cell culture techniques. The proliferative effect of SMOC2 on cells was evaluated using CCK- 8 assay, while the expression of SMOC2 and epithelial-mesenchymal transition (EMT) was assessed using real-time PCR and western blot analysis. RESULTS: SMOC2 expression was significantly higher in the ectopic endometrial tissue of adenomyosis patients compared to controls. SMOC2 could promote cell proliferation. Overexpression of SMOC2 significantly upregulated mesenchymal markers N-cadherin and α-SMA, and downregulated epithelial marker E-cadherin. Conversely, knocking down SMOC2 with siRNA reversed these effects. These findings indicate that SMOC2 promotes EMT in adenomyotic stromal cells. Additionally, SMOC2 also activated the MMP9 signaling pathway, which plays a crucial role in the extracellular matrix (ECM) remodeling. CONCLUSIONS: SMOC2 appears to be a key regulator in the pathogenesis of adenomyosis, promoting ECM remodeling and EMT, both of which are characteristic of the disease. Targeting SMOC2 may provide a novel therapeutic strategy for the treatment of adenomyosis.