Abstract

 

Nuclear factor erythroid 2-related factor 2 (Nrf2) provides cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist verapamil is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity through degradation of Kelch-like ECH-associated protein 1 (Keap1), an Nrf2 repressor. Furthermore, verapamil-induced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen-induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms of the protective role of verapamil against acetaminophen-induced cytotoxicity.