RSPO1–LGR4 axis drives cervical cancer progression via activation of the EGFR/Src/ERK/AKT signaling pathway

Cervical cancer (CCa) is a leading cause of cancer-associated mortality among women globally, posing a substantial health burden, particularly in low- and middle-income countries where HPV vaccination coverage remains limited. Therefore, identifying novel therapeutic targets to improve clinical outcomes is an urgent clinical need. R-spondin 1 (RSPO1) is a potent activator of Wnt/β-catenin signaling and has emerged as a potential driver of tumorigenesis, yet its biological function in cervical cancer remains poorly understood. In this study, we found that RSPO1 expression is upregulated in cervical cancer tissues, and its expression level is significantly associated with adverse clinical phenotypes in cervical cancer patients. Both in vitro and in vivo experiments demonstrate that overexpression of RSPO1 markedly enhances the proliferation, migration, invasion, and tumorigenic potential of cervical cancer cells. RSPO1 promotes cervical cancer progression by activating the EGFR/Src/ERK/AKT signaling axis in an LGR4-dependent manner. Mechanistically, the RSPO1–LGR4 complex facilitates plasma membrane recruitment of EGFR and Src for activation. Meanwhile, the RSPO1-promoted interaction between LGR4 and EGFR competitively blocks c-Cbl-mediated ubiquitination and subsequent degradation of EGFR. This dual regulatory mechanism mediates sustained activation of the EGFR/Src complex and its downstream ERK/AKT signaling cascades, ultimately driving progression of cervical cancer. In conclusion, our findings demonstrate that the RSPO1–LGR4 signaling axis plays a critical role in malignant progression of cervical cancer, suggesting that targeting this axis may be a promising therapeutic strategy for cervical cancer intervention.