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

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. Overall design: RNA-seq were conducted for the liver tissues or tumros of 10-month-old Tsc1f/f wild-type, Tsc1f/fAlbCre+, and Tsc1f/fAlbCre+/Nrf2-/- mice.