Targeting the LRIG2–PI3K/AKT/mTOR Axis to Induce Apoptosis: A Novel Antitumor Mechanism of Verbascoside in Endometrial Cancer Cells

<h3>Background/Aim:</h3> Endometrial cancer (EC) is a prevalent gynecological malignancy with increasing incidence worldwide. Despite advances in therapy, drug resistance remains a major challenge. Verbascoside, a natural phenylethanoid glycoside, possesses various pharmacological activities, including antitumor effects. However, its specific mechanism against EC, particularly the role of leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) in modulating apoptosis, remains poorly understood. <h3>Materials and Methods:</h3> We used <i>in vitro</i> and <i>in vivo</i> models to evaluate the antitumor efficacy of verbascoside. <i>In vitro</i>, the Ishikawa cell line was treated with verbascoside to assess cell viability and apoptosis. Molecular techniques, including western blotting, quantitative polymerase chain reaction, and immunofluorescence, were employed to analyze the expression levels of LRIG2, key proteins in the PAM pathway, and apoptosis markers. We also performed gene knockdown of <i>LRIG2</i> to confirm its regulatory role. The antineoplastic activity of verbascoside was evaluated using a mouse xenograft model. <h3>Results:</h3> Our findings demonstrate that verbascoside significantly inhibited proliferation and induced apoptosis of Ishikawa cells. Mechanistically, verbascoside treatment led to an increase in LRIG2 expression, which in turn inhibited activation of the PAM signaling pathway. <h3>Conclusion:</h3> This study identifies a subtype-specific mechanism whereby verbascoside suppresses tumor progression in both type I and type II EC models by upregulating LRIG2, which subsequently inactivates the PAM pathway to promote apoptosis. These findings highlight verbascoside as a promising therapeutic candidate for specific aggressive EC molecular subtypes.