Fig. 2.

Fumarate promotes treatment resistance through Nrf2 upregulation. Under homeostatic conditions, Keap1 binds to Nrf2 and promotes its ubiquitination and proteasomal degradation. Fumarate can abrogate the interaction between Keap1 and Nrf2 by modifying cysteine residues on Keap1. Subsequently, Nrf2 is translocated to the nucleus to promote the transcription of genes that inhibit apoptosis and promote drug resistance. Additionally, Nrf2 promotes OXPHOS which may restore metabolic flexibility. Abbreviations: Keap1 (Kelch ECH associating protein 1), Nrf2 (nuclear factor erythroid 2–related factor 2), ARE (antioxidant response element), OXPHOS (Oxidative phosphorylation). Figure created using BioRender