FNDC1 Competitively Binds Gβ2 to Suppress the β‐Catenin–Destruction Complex and Promote Gastric Cancer Malignancy

Gastric cancer (GC) is a leading cause of cancer‐related deaths and has high recurrence rate. Although fibronectin domain‐containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi‐omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co‐IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β‐catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224–254) of Gβ2, disrupting Gβγ–Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β‐catenin–destruction complex (GSK3 β–APC–Axin1), leading to β‐catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2–Dvl1 axis to activate Wnt/β‐catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target. FNDC1 competitively binds Gβ2 to suppress the β‐catenin–destruction complex and promote the malignant behavior of gastric cancer (GC) by the following mechanism: elevated FNDC1 competes with Dvl for binding to Gβ2, thereby reducing Dvl–Gβ2 interaction; this reduction inhibits Dvl degradation in the cytoplasm; increased Dvl recruits Axin1, thereby disrupting the β‐catenin–destruction complex (GSK3β–APC–Axin) and blocking ubiquitination and degradation of β‐catenin; accumulated β‐catenin in the cytoplasm translocates to the nucleus, where it activates Wnt target genes and promotes epithelial–mesenchymal transition (EMT) in GC cells.