Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4

Area of Science:

• Biochemistry
• Oncology
• Pharmacology

Background:

• Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide.
• Ferroptosis, a form of regulated cell death, presents a promising therapeutic strategy for GC.
• Myricetin, a natural flavonoid, possesses known anticancer properties but its role in ferroptosis remains unexplored.

Purpose of the Study:

• To investigate the effect of myricetin on ferroptosis in gastric cancer progression.
• To elucidate the underlying molecular mechanisms of myricetin-induced ferroptosis in GC cells.

Main Methods:

• In vitro studies using GC cell lines to assess ferroptosis markers (malondialdehyde, Fe2+ accumulation, glutathione levels).
• Investigation of myricetin's interaction with NADPH oxidase 4 (NOX4) and its effect on NOX4 stability.
• Analysis of the NOX4/NRF2/GPX4 pathway in response to myricetin and Helicobacter pylori CagA.
• In vivo experiments using a mouse xenograft model to evaluate myricetin's anti-tumor efficacy.

Main Results:

• Myricetin induced ferroptosis in GC cells by increasing malondialdehyde and Fe2+ levels, and decreasing glutathione.
• Myricetin directly bound to NOX4, inhibiting its ubiquitin degradation and enhancing its stability.
• Myricetin counteracted the ferroptosis inhibition induced by H. pylori CagA via the NOX4/NRF2/GPX4 pathway.
• In vivo, myricetin significantly suppressed tumor growth in mice, correlating with increased NOX4 and decreased NRF2/GPX4 pathway activity.

Conclusions:

• Myricetin acts as a novel ferroptosis inducer in gastric cancer cells through direct interaction with NOX4.
• Myricetin demonstrates significant anti-tumor effects in vivo, highlighting its potential as a therapeutic agent for GC.
• Targeting the NOX4/NRF2/GPX4 pathway with myricetin offers a promising strategy for gastric cancer treatment.