LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway

Background: Polycystic ovary syndrome (PCOS), which is often accompanied by insulin resistance, is closely related to increased apoptosis of ovarian granulosa cells. LNK is an important regulator of the insulin signaling pathway. When insulin binds to the receptor, the PI3K/AKT/FOXO signaling pathway is activated, and FOXO translocates from ine nucleus to the cytoplasm, thereby inhibiting the expression of pro-apoptotic genes. Methods: Granulosa cells were collected from PCOS patients to investigate the relationship between LNK, cell apoptosis and insulin resistance. KGN cells underwent LNK overexpression/silence and insulin stimulation. The AKT/FOXO3 pathway was studied by western blot and immunofluorescence. LNK knockout mice were used to investigate the effect of INK on the pathogenesis of PCOS. Results: The level of LNK was nigher in PCOS group than control group. LNK was positively correlated with granulosa cell apoptosis and insulin resistance, and negatively correlated with oocre maturation rate. LNK overexpression in KGN cells insulin-induced AKT/FOXO3 signaling pathway, causing nucleus translocation of FOXO3 and promoting granulosa cell apoptosis. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice. Conclusions: LNK was closely related to insulin resistance and apoptosis of granulasa cells via the AKT/FOXO3 pathway. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice, suggesting LNK might become a potential biological target for the clinical treatment of PCOS.

Automated summary

The study revealed that LNK was higher in the PCOS group compared to the control group, positively correlated with granulosa cell apoptosis and insulin resistance, and negatively correlated with follicle maturation rate. Overexpression of LNK in KGN cells induced the AKT/FOXO3 signaling pathway in response to insulin, leading to FOXO3 translocation to the nucleus and promotion of granulosa cell apoptosis. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice.