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Tamarixetin induces ferroptotic stress through the SLC7A11–GPX4 axis and triggers a compensatory NRF2 response

ABSTRACT: Ferroptosis has emerged as a therapeutic vulnerability in hepatocellular carcinoma, but its interplay with antioxidant defense remains incompletely understood. Here, we investigated whether Tamarixetin induces ferroptotic stress in hepatoma cells and how nuclear factor erythroid 2-related factor 2 (NRF2) signaling responds to this process. Tamarixetin selectively reduced hepatoma cell viability, increased lipid peroxidation, and these effects were partially rescued by ferrostatin-1. Transcriptome analysis revealed enrichment of ferroptosis- and glutathione metabolism-related pathways, highlighting redox-associated genes centered on the SLC7A11–glutathione peroxidase 4 (GPX4) axis. Tamarixetin also increased NRF2 target gene expression, indicating activation of a compensatory antioxidant response to oxidative stress. Molecular docking further suggested a potential interaction between Tamarixetin and the xCT transporter. These findings identify Tamarixetin as a modulator of ferroptotic stress in hepatoma cells and support redox-targeting strategies for liver cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327198 | GEO | 2026/05/11

REPOSITORIES: GEO

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Project description:Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. While ferroptosis has been identified as a mechanism for suppressing cancer, its overall physiological significance remains poorly understood. Recent studies have revealed that labile iron and lipid peroxides are released from ferroptotic cells, leading to the propagation of ferroptosis through lipid peroxidation. However, other specific effects of secreted factors derived from ferroptotic cells remain unclear. We constructed a model cell system capable of inducing ferroptosis by re-expressing the transcription factor BACH1, a potent inducer of ferroptosis, in immortalized mouse embryonic fibroblasts (iMEFs). We investigated the impact of the secreted factors from ferroptotic cells with the iMEFs. As a result, we observed that the administration of supernatant media from ferroptotic iMEFs activated proliferation of hepatoma cells and suppressed cellular senescence-like features. This suggested that ferroptotic MEFs secrete anti-senescent substances. Transcriptome analysis of ferroptotic MEFs revealed an increase in the secretion of longevity factor FGF21 in a BACH1-dependent manner. Furthermore, the anti-senescent effects of the supernatant media from these ferroptotic cells were canceled by the knockout of Fgf21. Totally, it is suggested that BACH1 promotes ferroptosis in fibroblasts and contributes to the suppression of cellular senescence in neighboring cells by inducing FGF21 secretion from fibroblasts. It was also discovered that BACH1 not only activates indirectly the transcription of FGF21 by enhancing ferroptotic stress but also increases FGF21 protein level by suppressing the selective autophagic degradation of FGF21 through the transcriptional repression for Sqstm1 and Lamp2a. This represents a dual mechanism of FGF21 upregulation mediated by BACH1, suggesting that BACH1 is a potent inducer of FGF21 expression. It was also found that the BACH1-ferroptosis-FGF21 axis can suppress obesity of mice under high fat diet or short lifespan of progeria mice, closely associated phenotypes with aging. The inhibition of these aging-related phenotypes is considered to be a novel physiological significance of ferroptosis, and BACH1 is considered to function as a longevity gene by promoting ferroptotsis and subsequent FGF21 expression.

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Tamarixetin induces ferroptotic stress through the SLC7A11–GPX4 axis and triggers a compensatory NRF2 response

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