A targetable ALDH3A2-NRF2 axis mediates KEAP1-mutant tumour development via ferroptosis inhibition

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of the cellular antioxidant response that defends against ferroptosis and facilitates tumour development. Here, by performing an aldehyde dehydrogenase (ALDH) family shRNA screen, our study identifies aldehyde dehydrogenase 3 family member A2 (ALDH3A2) as a potent NRF2 activator that inhibits ferroptosis. Interestingly, ALDH3A2 efficiently activates NRF2 in both wild-type (WT) Kelch-like ECH-associated protein 1 (KEAP1) and mutant KEAP1 tumour cells. Mechanistically, ALDH3A2 inhibits the phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and blocks recruitment of E3 ubiquitin ligase beta-transducin repeat-containing protein (BTRC) to NRF2, thereby stabilizing NRF2 by preventing its proteasomal degradation. Knockdown of ALDH3A2 significantly promotes the activation of the GSK3β signaling pathway and accelerates NRF2 degradation. ALDH3A2 stabilizes NRF2 independently of its enzymatic activity, as enzymatic inactivation of ALDH3A2 fails to block ALDH3A2-mediated NRF2 activation and ferroptosis suppression both in vitro and in vivo. Taken together, our study reveals a novel NRF2 regulatory pathway and suggests ALDH3A2 as a promising druggable target for KEAP1-mutant tumours.