Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer

TLDR

Cancer cells’ high metabolic demand generates reactive oxygen species, prompting hyperactivation of the NRF2 antioxidant pathway to sustain growth, yet the metabolic vulnerabilities arising from this reprogramming remain poorly understood. NRF2 activation forces cancer cells to rely on exogenous glutamine, diverting glutamate to glutathione synthesis and xc‑antiporter secretion, which depletes TCA cycle intermediates and creates a metabolic bottleneck that can be therapeutically targeted.

Abstract

During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc- antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited.