The Activation of the Transcription Factor NRF2 in Epithelial Cells Lining the Kidney Cysts in Tuberous Sclerosis Complex (TSC): The Interplay of Fumarate Hydratase 1, KEAP1, and NRF2 in Kidney Cystogenesis

The preprint describes NRF2 activation as a survival programme in tuberous sclerosis complex kidney cysts, reached through KEAP1 succination rather than through mutation. The single NFE2L2 entry in the Claidex graph, MGY825 in NFE2L2, KEAP1 or CUL3 mutant non-small cell lung cancer, was closed as a strategic termination in Phase 1 without an efficacy readout (mgy825-nfe2l2-nrf2-mutant-nsclc-phase1-strategic-termination), so the record says little about whether the pathway is drugable in patients. The relevant caution is about patient selection rather than about the biology. A mutation-defined enrichment strategy does not capture cells where NRF2 is activated post-translationally, which is the state described here, and any therapeutic programme built on this finding would need a functional readout of NRF2 activity rather than a genotype to identify the right tissue.