Synergistic antitumor effects of Phlorizin and Temozolomide in glioblastoma: Mechanistic insights and molecular targeting.

Glioblastoma (GBM), one of the most aggressive brain cancers, presents significant treatment challenges due to its complex biology and resistance to conventional therapies, necessitating the development of new, low-toxicity, and effective treatments. This study explores the antitumor potential of phlorizin, a naturally occurring dihydrochalcone, as a standalone agent and in combination with temozolomide (TMZ), the standard chemotherapeutic for GBM. Phlorizin was found to significantly inhibit cell viability and migration in vitro, with synergistic effects observed when combined with TMZ. Comprehensive analyses, including protein-protein interaction network construction, enrichment analysis, and molecular docking with AKT1, identified the PI3K/AKT/mTOR signaling pathway as a critical mediator of glioblastoma cell survival and proliferation targeted by phlorizin. Pathway enrichment analysis of 88 intersection targets further highlighted this pathway's role in phlorizin's activity. Western blot validation confirmed that phlorizin inhibits the expression of key proteins within the PI3K/AKT/mTOR pathway, providing a mechanistic basis for its antitumor effects. These findings suggest that phlorizin, particularly in combination with TMZ, holds significant potential as a therapeutic strategy for glioblastoma by targeting molecular pathways critical for cancer cell survival and proliferation.