The lethality and hyperkeratosis is nicely rescued by simultaneous systemic Nrf2 knockout (Keap1–/–::Nrf2–/–) [52] or keratinocyte-specific Nrf2 knockout (Keap1–/–::Nrf2flox/flox::Keratin5-Cre) [90], clearly demonstrating that esophageal hyperkeratosis is provoked by constitutive and massive NRF2 activation as a consequence of Keap1 deletion. This evidence concerns the gene KEAP1 and Hyperkeratosis.