Brusatol, an NRF2 inhibitor for future cancer therapeutic

Schematic illustration of brusatol anticancer effect by inhibiting NRF2 activity. NRF2 is the key transcription factor regulating oxidative homeostasis. In normal cells, NRF2 is recognized by KEAP1 for ubiquitination and degradation. Oxidative stress compromises the function of KEAP1, allowing the stabilization and transcriptional activity of NRF2. The expression of NRF2 downstream genes maintain the oxidative homeostasis and cell survival. Cancer cells tend to exhibit constitutive NRF2 activity through intrinsic oxidative stress and KEAP1 mutations, and therefore support tumor expansion and therapy resistance. Brusatol inhibits NRF2 by enhancing protein ubiquitination, resulting in the disrupted redox balance, cell death and tumor suppressio