Ferroptosis holds great potential as a therapeutic approach for gastric cancer (GC), a prevalent and deadly malignant tumor associated with high rates of incidence and mortality. Myricetin, well-known for its multifaceted biomedical attributes, particularly its anticancer properties, has yet to be thoroughly investigated regarding its involvement in ferroptosis. The aim of this research was to elucidate the impact of myricetin on ferroptosis in GC progression. The present study observed that myricetin could trigger ferroptosis in GC cells by enhancing malondialdehyde production and Fe²⁺ accumulation while suppressing glutathione levels. Mechanistically, myricetin directly interacted with NADPH oxidase 4 (NOX4), influencing its stability by inhibiting its ubiquitin degradation. Moreover, myricetin regulated the inhibition of ferroptosis induced by Helicobacter pylori cytotoxin-associated gene A (CagA) through the NOX4/NRF2/GPX4 pathway. In vivo experiments demonstrated that myricetin treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice. It was accompanied by increased NOX4 expression in tumor tissue and suppression of the NRF2/GPX4 antioxidant pathway. Therefore, this research underscores myricetin as a novel inducer of ferroptosis in GC cells through its interaction with NOX4. It is a promising candidate for GC treatment.

中文翻译：

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杨梅素通过靶向 NOX4 诱导铁死亡并抑制胃癌进展

铁死亡作为胃癌（GC）的治疗方法具有巨大潜力，胃癌是一种流行且致命的恶性肿瘤，发病率和死亡率很高。杨梅素以其多方面的生物医学特性，特别是其抗癌特性而闻名，但其与铁死亡的关系尚未得到彻底研究。本研究的目的是阐明杨梅素对 GC 进展中铁死亡的影响。本研究观察到杨梅素可以通过增强丙二醛的产生和Fe ²⁺的积累同时抑制谷胱甘肽水平来引发GC细胞的铁死亡。从机制上讲，杨梅素直接与 NADPH 氧化酶 4 (NOX4) 相互作用，通过抑制其泛素降解来影响其稳定性。此外，杨梅素通过NOX4/NRF2/GPX4途径调节对幽门螺杆菌细胞毒素相关基因A（CagA）诱导的铁死亡的抑制。体内实验表明，杨梅素治疗显着抑制BALB/c裸鼠皮下肿瘤的生长。伴随着肿瘤组织中 NOX4 表达的增加和 NRF2/GPX4 抗氧化途径的抑制。因此，本研究强调杨梅素通过与 NOX4 相互作用，成为 GC 细胞铁死亡的新型诱导剂。它是 GC 治疗的一个有前途的候选者。