Compensation for impaired sensing of selenoprotein deficiency by alternative cysteine residues in KEAP1

The KEAP1-NRF2 system is a master regulator of cellular defense against oxidative and electrophilic stresses. Cysteine residues within KEAP1 function as critical stress sensors. While KEAP1-Cys151 is a well-established sensor for electrophilic NRF2 activators, its contribution to the oxidative stress response remains unclear. Here, we investigated NRF2 activation in Cys151-deficient mice under hepatocyte-specific disruption of selenoprotein synthesis, a condition associated with profound redox imbalance. NRF2 activation and hepatic homeostasis were preserved in these mice, indicating that Cys151 is dispensable for sensing of selenoprotein deficiency. Conversely, loss of Cys226/Cys613-mediated sensing impaired NRF2 activation, leading to severe liver injury and lethality. Importantly, treatment with the Cys151-dependent electrophilic activator CDDO-Im restored NRF2 activity and improved survival in mice lacking functional Cys226/Cys613 sensing. Together, these findings demonstrate that individual KEAP1 cysteine residues have distinct functional roles in stress sensing, yet their signals converge on a common pathway to regulate NRF2 activation.