This suggests that somatic activation of NRF2 may not be tolerated in tRCC owing to their dependence on aerobic respiration, as such events would be predicted to constrain aerobic respiration, upset NADH/NAD+ balance, and result in NADH-reductive stress41,104. Here, NFE2L2 is linked to renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions.