10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.

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.