The physiological risks of constitutive NRF2 activation due to loss of KEAP1 binding have been demonstrated in vivo through KEAP1 knockout mice, which die from starvation shortly after birth from hyperkeratosis of the gastrointestinal tract, likely through overexpression of α-keratins and loricrins in squamous cells (ref. 38; Fig. 4c). This evidence concerns the gene NFE2L2 and Hyperkeratosis.