Natural Product Daidzin Inhibits Glioma Development via Suppressing the LRP5‐Mediated GSK‐3β/c‐Myc Signaling Pathway

ABSTRACT Daidzin (DZN) is a natural flavonoid compound derived from soybeans that has recently been recognized for its potential antitumor properties. In traditional Chinese medicine, soybeans and their extracts are extensively used to prevent and treat various diseases. To evaluate the therapeutic efficacy of DZN on human glioblastoma through in vivo and in vitro experiments, and through multi‐omics analyses to elucidate potential molecular mechanisms. Cell viability of LN‐229 and U‐87MG glioblastoma cells was assessed using the CCK‐8 assay. Protein and mRNA levels of proliferation and apoptosis‐related genes were analyzed via Western blotting and qPCR. Metabolomics and transcriptomics identified key pathways and targets, which were confirmed by in‐cell Western blotting and expression correlation analysis. The in vivo antitumor effects of DZN were evaluated in nude mice with LN‐229 tumors. DZN treatment reduced cell viability, migration, and survival in a dose‐dependent manner, demonstrating strong antitumor effects in both in vitro and in vivo models. Multi‐omics analysis identified amino acid metabolism and ubiquitin‐mediated proteolysis as key mechanisms. Bioinformatics highlighted LRP5 as a prognostic biomarker in glioblastoma. DZN decreased LRP5 activity, downregulated p‐GSK‐3 β , and promoted c‐Myc degradation, thereby inhibiting the Wnt signaling pathway. In vivo, DZN significantly reduced tumor size and Ki67 expression. These findings highlight LRP5 as a promising therapeutic target, with DZN emerging as a potent LRP5 inhibitor and exhibiting significant antitumor effects in glioblastoma.