A rare germline mutation reverses the suppressive effect of GPC5 thereby promoting lung adenocarcinoma development and tumorigenesis

Our findings establish that the GPC5 c.776C>T mutation drives LUAD progression through a novel molecular mechanism involving impaired β-catenin degradation, subsequent nuclear translocation, and consequent EMT activation. These results position GPC5 as a critical nodal regulator of Wnt/β-catenin signaling in LUAD pathogenesis and suggest its germline mutations may serve as valuable biomarkers for hereditary LUAD risk assessment. Therapeutically, these findings highlight the potential utility of Wnt pathway inhibitors in managing GPC5-mutant LUAD cases, while also providing a molecular framework for future investigations into glypican family members in cancer biology.