Knockdown of TSP ‐4 Promotes Proliferation, Migration, Glucose Uptake, and Inhibits Inflammatory Damage in Trophoblast Cell Lines Exposed to High Glucose

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy-related condition that poses risks to both the mother and the fetus. Although dysregulated thrombospondin-4 (TSP-4) has been observed in women with GDM, the precise role of TSP-4 in the pathogenesis of GDM remains unclear. This study investigates the role of TSP-4 in regulating trophoblast function under high glucose (HG) conditions. METHODS: HTR-8/SVneo cells were exposed to HG to establish an in vitro GDM model. TSP-4 expression was silenced via lentiviral transfection. The effects of TSP-4 knockdown on cell proliferation, migration, invasion, inflammation, and the PI3K/Akt/mTOR signaling pathway were assessed using Western blotting, Cell Counting Kit-8 assay, glucose uptake assay, enzyme-linked immunosorbent assay (ELISA), and Transwell assay. RESULTS: HG exposure significantly upregulated TSP-4 expression in HTR-8/SVneo cells. TSP-4 knockdown under HG conditions enhanced cell migration, invasion, proliferation, and glucose uptake. Furthermore, TSP-4 knockdown inhibited the inflammatory response in HG-treated HTR-8/SVneo cells in the HG group. Notably, TSP-4 knockdown also modulated the activation of the PI3K/Akt/mTOR signaling pathway. CONCLUSION: TSP-4 knockdown promotes proliferation, migration, glucose uptake, reduces inflammation, and regulates the expression of the PI3K/Akt/mTOR signaling pathway in trophoblast cell lines under HG conditions, suggesting a potential role for TSP-4 in the pathophysiology of GDM.