10 Gingerol通过TFEB介导的NRF2溶酶体降解在NSCLC中诱导铁下垂
10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.
摘要(中文译文)
10-姜辣素(10-G)具有抗肿瘤活性,但其在非小细胞肺癌(NSCLC)中的作用机制尚不清楚。铁死亡是一种由脂质过氧化引起的程序性细胞死亡方式,受抗氧化系统异常和铁代谢的调控。本研究探讨了10-G在NSCLC中的抗肿瘤机制,重点强调其在激活溶酶体和诱导铁死亡中的双重作用。在本研究中,我们发现10-G通过增加铁蓄积、脂质过氧化、细胞内ROS水平以及丙二醛(MDA)生成,同时消耗谷胱甘肽(GSH)并升高Fe水平,从而诱导NSCLC发生铁死亡。在机制上,10-G诱导转录因子EB(TFEB)去磷酸化并使TFEB与14-3-3蛋白解离,从而促进TFEB的核转位及溶酶体基因表达的激活。随后,溶酶体的激活促进了核因子E2相关因子2(NRF2)的降解,从而影响下游靶点谷胱甘肽过氧化物酶4(GPX4)和胱氨酸/谷氨酸逆向转运蛋白SLC7A11(xCT)的表达水平,最终导致铁死亡。在体内,10-G通过抑制TFEB介导的NRF2/xCT/GPX4轴并促进铁死亡,从而抑制肿瘤生长。这些发现表明,10-G通过促进TFEB介导的NRF2溶酶体降解,进而诱导铁死亡,从而抑制NSCLC的进展,这为一种新的潜在治疗策略提供了理论依据。
Abstract
10-Gingerol (10-G) exhibits antitumor activity, yet its mechanism in non-small cell lung cancer (NSCLC) remains unclear. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. This study investigated the antitumor mechanism of 10-G in NSCLC, emphasizing its dual role in activating lysosomes and inducing ferroptosis. In this study, we found 10-G induced ferroptosis in NSCLC by increasing iron accumulation, lipid peroxidation, intracellular ROS levels, and malondialdehyde (MDA) production, while depleting glutathione (GSH) and rising Fe levels. Mechanistically, 10-G induced the dephosphorylation of Transcription Factor EB (TFEB) and TFEB dissociation from the 14-3-3 protein, thereby promoting the nuclear translocation of TFEB and the activation of lysosomal gene expression. Subsequently, the activation of lysosomes promoted the degradation of Nuclear factor erythroid 2-related factor 2 (NRF2), thereby affecting the expression levels of downstream targets Glutathione Peroxidase 4 (GPX4) and cystine/glutamate antiporter SLC7A11 (xCT), ultimately leading to ferroptosis. In vivo, 10-G suppressed tumor growth by inhibiting the TFEB-mediated NRF2/xCT/GPX4 axis and promoting ferroptosis. These findings demonstrated that 10-G suppressed the progression of NSCLC by promoting TFEB-mediated lysosomal degradation of NRF2, thereby inducing ferroptosis, which provides a rationale for a novel potential therapeutic strategy.
如何引用
AMA
Siying Li, Kaihua Shi, Lei Huang, Ziqing Li, Zhuo Qin, Yanan Sun, et al. 10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.. Toxicology and applied pharmacology. 2026; doi:10.1016/j.taap.2026.117828.
APA
Siying Li, Kaihua Shi, Lei Huang, Ziqing Li, Zhuo Qin, Yanan Sun, et al (2026). 10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.. Toxicology and applied pharmacology. https://doi.org/10.1016/j.taap.2026.117828
GB/T 7714
Siying Li, Kaihua Shi, Lei Huang, Ziqing Li, Zhuo Qin, Yanan Sun, et al. 10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.[J]. Toxicology and applied pharmacology, 2026 doi:10.1016/j.taap.2026.117828.
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