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Nrf2 ablation abolishes liver tumorigenesis by suppressing L-2-hydroxyglutarate-driven regulation of ferroptosis in a spontaneous liver tumor model induced by hepatic Tsc1 deletion

ABSTRACT: The metabolite L-2-hydroxyglutarate (L2HG) regulates liver tumor development through both anti- and pro-ferroptotic mechanisms, mediated via the Nrf2/Slc7a11 and Atf4/Chac1 signaling axes. To investigate the essential role of Nrf2 in L2HG-driven ferroptosis regulation, we analyzed gene expression profiles in liver tumors from Tsc1f/f wild-type, Tsc1f/fAlbCre+, and Tsc1f/fAlbCre+/Nrf2-/- mice. We found that the ferroptosis-related transcriptome in Tsc1f/fAlbCre+/Nrf2-/- mice more closely resembled that of tumor-free Tsc1f/f wild-type mice than the tumor-bearing Tsc1f/fAlbCre+ cohort. These findings demonstrate that Nrf2 ablation disrupts L2HG-induced cystine uptake via the xCT antiporter system, rewires metabolic pathways, and restores ferroptotic sensitivity. This metabolic reprogramming effectively suppresses liver tumor development in vivo, underscoring the critical oncogenic interplay between L2HG metabolism and Nrf2-mediated ferroptosis resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE301997 | GEO | 2025/07/26

REPOSITORIES: GEO

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Project description:Background/Objectives: Ferroptosis, an iron-dependent form of cell death, shows promise as a target for therapy-resistant cancers that exhibit increased iron metabolism. Ferroptosis is primarily characterised by lipid peroxidation within cell membranes. However, many cancers evade ferroptosis by upregulation of specialised ferroptosis defence mechanisms. This study investigates ferroptosis susceptibility in Tuberous Sclerosis Complex (TSC) cell models, and ovarian and breast cancer cell lines to identify ferroptosis resistance mechanisms and therapeutic targets. Methods: We assessed ferroptosis susceptibility using the ferroptosis inducers, RSL3 and erastin. We explored ferroptosis resistance genes using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA-sequencing was conducted to identify dysregulated ferroptosis resistance genes and to better characterise NRF2 target genes. RNA sequencing was also performed to identify gene expression after treatment with pro-ferroptotic iron-oxide nanoparticles. Results: TSC2-deficient cells exhibited resistance to RSL3 and erastin-induced ferroptosis, which correlated with increased ferroptosis defence gene expression, including NRF2 and downstream targets. NRF2 inhibition re-sensitised TSC2-deficient cells to ferroptosis, confirming its protective role. However, FSP1 inhibition did not re-sensitise TSC2-deficient angiomyolipoma kidney tumor cells to RSL3. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cell lines. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition in reversing ferroptosis resistance. Conclusions: Our findings highlight NRF2 and FSP1 as key regulators of ferroptosis resistance in TSC2-deficient and cancer cells. However, the differential efficacy of targeting these pathways suggests that patient stratification may be necessary for optimal therapeutic strategies. Targeting NRF2 and FSP1 could enhance ferroptosis susceptibility, offering a potential therapeutic approach for ferroptosis resistance cancers.

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Nrf2 ablation abolishes liver tumorigenesis by suppressing L-2-hydroxyglutarate-driven regulation of ferroptosis in a spontaneous liver tumor model induced by hepatic Tsc1 deletion

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