Inhibition of gastric adenocarcinoma proliferation by WSGC@MS: Role of KEAP1/NRF2 signaling pathway and autophagy regulation

Porous Magnetic Chitosan Microspheres (MS) serve as effective carriers for targeted drug delivery due to their magnetic properties and biocompatibility. This study investigates the therapeutic potential of WSGC Peptide-loaded porous MS (WSGC@MS) in treating gastric adenocarcinoma by elucidating its mechanism of action in inhibiting cancer cell proliferation. The prepared porous MS was characterized using various techniques, and the physicochemical properties of the nanocomposites were evaluated. In vitro experiments demonstrated that WSGC@MS effectively suppressed the proliferation of gastric adenocarcinoma cells, enhanced apoptosis, and increased cellular uptake and reactive oxygen species production under magnetic field exposure. <i>In vivo</i> studies in a gastric adenocarcinoma mouse model revealed significant accumulation of WSGC@MS at tumor sites, resulting in substantial inhibition of tumor growth and metastasis. Transcriptomic analysis uncovered the downregulation of FAM117B, inhibition of the KEAP1/NRF2 pathway, and activation of autophagy mediated by ROS/AMPK/mTOR. Overall, WSGC@MS shows great promise for targeted therapy in gastric adenocarcinoma by degrading NRF2 ubiquitination, regulating the KEAP1/NRF2 signaling pathway, and inducing autophagy, offering a novel nanotechnology-based treatment strategy.