While in cancers featuring FH downregulation (such as HLRCC) the accumulation of fumarate is the main cause of NRF2 hyperactivation through the post-translational modification of its regulatory proteins [20,66], NRF2 signature regulation in sporadic forms of RCCs is more complex. This evidence concerns the gene NFE2L2 and hereditary leiomyomatosis and renal cell cancer.