Identification of narciclasine as a novel NRF2 inhibitor

Cancer genome sequencing studies have identified somatic mutations in the KEAP1/NRF2 pathway. In an effort to identify novel NRF2 small molecule inhibitor(s), we have screened a natural compound library comprising 1330 chemicals in A549-ARE-GFP-luciferase cells and identified that narciclasine significantly inhibits NRF2-dependent luciferase activity. Narciclasine suppressed the expression of NRF2 and NRF2 target genes, caused significant oxidative stress, and sensitized cisplatin-mediated apoptosis in A549 cells. In addition, we have observed that WD Repeat Domain 43 (WDR43) serves as a direct target of narciclasine for the inhibition of NRF2 as narciclasine binds to recombinant WDR43 <i>in vitro</i> and silencing <i>WDR43</i> attenuated the inhibition of NRF2 by narciclasine in A549 cells. Finally, we observed that administration of narciclasine significantly decreased the growth of A549 xenografts. Together, our results demonstrate that the inhibition of NRF2 by narciclasine is mediated by WDR43 and future studies are necessary to elucidate the exact mechanism of how WDR43 mediates the inhibition of NRF2 by narciclasine.