Naringenin, a Food-Derived Flavanone, Suppresses ITGA11-Associated Gastric Cancer Progression via the FAK/PI3K/AKT/mTOR Axis

(1) Background: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide. Aberrant remodeling of the extracellular matrix (ECM) is a hallmark of GC progression; however, the mechanisms by which GC cells sense and exploit ECM cues remain unclear. (2) Methods: ITGA11 was identified through integrative bioinformatic analyses. Its expression, clinical significance, and association with ECM-related signatures were evaluated in GC tissues and public datasets. The function of ITGA11 and its role in regulating the FAK/PI3K/AKT/mTOR pathway were investigated using in vitro and in vivo assays, and the inhibitory effect of Naringenin on ITGA11-associated oncogenic activity was assessed. (3) Results: ITGA11 was upregulated in GC tissues and correlated with an ECM-related gene signature, aggressive clinicopathological features and poor patient survival. ITGA11 promoted malignant phenotypes of GC cells in vitro and in vivo. Importantly, molecular docking and target engagement assays suggested a potential interaction between Naringenin and ITGA11. Functional experiments showed that Naringenin attenuated ITGA11-associated oncogenic activity by reducing ITGA11 levels, suppressing pathway activation, and inhibiting malignant phenotypes. (4) Conclusions: Our findings identify ITGA11 as a potential prognostic biomarker and functional driver of GC progression and suggest that Naringenin may represent a promising bioactive compound for modulating the ITGA11/FAK/PI3K/AKT/mTOR axis in GC.