SEMA3C Promotes the Progression of Endometriosis by Inducing Ferroptosis and Enhancing the Viability and Migration of Endometrial Stromal Cells

INTRODUCTION: Endometriosis (EMs) is a chronic inflammatory disorder involving ectopic endometrial-like tissue. Semaphorin 3C (SEMA3C), a secreted guidance protein regulating cell survival, migration, and tissue remodeling, may contribute to EMs. This study examined SEMA3C expression and its relationship with ferroptosis in human endometrial stromal cells (HESCs). METHODS: SEMA3C expression was assessed in tissues from 30 patients with EMs and 30 controls by immunohistochemistry, Western blotting, and quantitative real-time PCR. Primary HESCs were subjected to SEMA3C overexpression or siRNA-mediated knockdown. Cell viability, migration, iron content, lipid peroxidation, antioxidant activity, inflammatory cytokines, and ferroptosis regulators were analyzed. Ferrostatin-1 was used for rescue experiments. RESULTS: SEMA3C was upregulated in ectopic tissues versus controls (P < 0.001) and correlated with disease severity (stage III-IV vs. I-II, P < 0.01). Ectopic lesions also showed higher SEMA3C mRNA than matched eutopic endometrium (P < 0.001). Ectopic tissues and SEMA3C-overexpressing HESCs showed increased ferroptosis-related oxidative and inflammatory changes. SEMA3C overexpression enhanced HESC viability and migration, increased ACSL4, and decreased Nrf2, GPX4, and SLC7A11 expression (P < 0.001). SEMA3C knockdown or Ferrostatin-1 attenuated these alterations and suppressed HESC viability and migration (P < 0.01). CONCLUSION: SEMA3C promotes HESC viability and migration through ferroptosis-related oxidative and inflammatory mechanisms, identifying the SEMA3C-ferroptosis axis as a potential pathogenic pathway in EMs.