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. 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.

代谢物L-2-羟基戊二酸（L-2-hydroxyglutarate，L2HG）可通过抑制铁死亡（ferroptosis）与促进铁死亡的双重机制调控肝脏肿瘤发生，该过程由核因子E2相关因子2（Nrf2）/Slc7a11与激活转录因子4（Atf4）/Chac1信号轴介导。为探究Nrf2在L2HG介导的铁死亡调控中的核心作用，我们对Tsc1f/f野生型、Tsc1f/fAlbCre+及Tsc1f/fAlbCre+/Nrf2-/-三类小鼠的肝脏肿瘤组织进行了基因表达谱分析。研究显示，与荷瘤Tsc1f/fAlbCre+小鼠队列相比，Tsc1f/fAlbCre+/Nrf2-/-小鼠的铁死亡相关转录组特征与无瘤Tsc1f/f野生型小鼠更为接近。上述结果表明，Nrf2敲除可通过胱氨酸/谷氨酸反向转运蛋白（xCT）系统阻断L2HG诱导的胱氨酸摄取，重塑代谢通路并恢复铁死亡敏感性。该代谢重编程可在体内有效抑制肝脏肿瘤发生，凸显了L2HG代谢与Nrf2介导的铁死亡抵抗之间关键的致癌互作关系。本研究对10月龄的上述三类小鼠的肝脏组织及肿瘤组织开展了RNA测序（RNA-seq）。