Dioscin suppresses epithelial-mesenchymal transition in gastric cancer by upregulating Cx43 to inhibit the VEGFA/PI3K/Akt/mTOR pathway.

[BACKGROUND] Connexin 43 (Cx43) and Cx43-gap-junction-intercellular-communications (Cx43-GJs) play an important role in metastasis. While dioscin exhibits remarkable anticancer activities in various cancers, its effect on Cx43/Cx43-GJs in gastric cancer (GC) remains poorly understood.

[PURPOSE] This study aimed to elucidate the anti-metastatic efficacy and underlying mechanism of the plant-derived compound dioscin against gastric cancer cells.

[METHODS] We integrated network pharmacology, molecular docking, and dynamics simulations to identify targets. Using in vitro models (overexpression, G21R mutant, siRNA knockdown) and in vivo xenograft models, we assessed dioscin's effects on proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and signaling pathways via Western blot, immunofluorescence, wound healing, transwell, and co-immunoprecipitation assays.

[RESULTS] Bioinformatic analysis highlighted the VEGFA/PI3K/AKT/mTOR pathway as central to GC malignancy. Dioscin suppressed this axis in a time- and concentration-dependent manner by upregulating Cx43 and enhancing gap junction function. Loss-of-function (siRNA/G21R) and rescue experiments confirmed that functional Cx43 is essential for the efficacy of dioscin. The G21R mutant revealed the critical role of Cx43's scaffolding function in signaling regulation. Dioscin, via a Cx43-mediated "dual-barrier" mechanism-strengthening epithelial adhesion and triggering migration inhibition-effectively suppressed EMT and cell motility.

[CONCLUSION] This study elucidates a novel mechanism by which dioscin inhibits GC via Cx43-mediated suppression of VEGFA/PI3K/AKT/mTOR signaling and establishes Cx43 as a key nexus linking natural compounds to oncogenic pathways. The non-channel scaffolding function of Cx43 offers a new theoretical framework and therapeutic strategy for GC intervention.