Liposomal nanoparticle-encapsulated polyphenolic vitamins activate ferroptosis in glioma cells by suppressing the EGFR/NOTCH1/Hes1 pathway

Background: Vitamin phenol has anti-glioma potential but low bioavailability. Liposomal nanoparticles are effective drug delivery systems. Whether vitamin phenol-encapsulated liposomal nanoparticles can regulate ferroptosis in glioma cells remains unknown. Objectives: This study aims to investigate the role of polyphenolic vitamins-encapsulated liposomal nanoparticles in ferroptosis in glioma cells. Methods: LNP-Vig nanoparticles were prepared. U87MG cells were divided into control, LNP and LNP-Vig groups, with the latter receiving additional treatments (si-EGFR, pc-DNA EGFR, si-Hes1, or pc-DNA Hes1). Levels of ferroptosis, apoptosis and related proteins (EGFR/Hes1) were then detected. Results: The successfully formulated LNP-Vig nanoparticles induced ferroptosis and suppressed EGFR expression in U87MG cells, leading to increased apoptosis upon prolonged incubation. While si-EGFR reduced EGFR mRNA, the pc-DNA EGFR counteracted LNP-Vig's suppression of EGFR. The consistent changes in downstream NOTCH1 and Hes1 mRNA levels confirmed that LNP-Vig influences the NOTCH1/Hes1 pathway via EGFR inhibition. Both NOTCH1 blockade and Hes1 knockdown reduced the levels of ferroptosis-related proteins, whereas NOTCH1 activation or Hes1 overexpression inhibited ferroptosis (P<0.05). Conclusion: LNP-Vig promotes apoptosis by activating ferroptosis, an effect crucially dependent on Hes1 suppression. By modulating the EGFR/NOTCH1 pathway, LNP-Vig promotes ferroptosis in U87MG cells, thus identifying a potential new target for cancer treatment.