NRF2 and mutant p53 separately regulate redox balance in esophageal squamous cell carcinoma through metabolic reprogramming

Background Alterations in CUL3-KEAP1-NFE2L2 (CKN) axis and p53 lead to abnormal NRF2 activation and p53 dominant-negative (p53DN) effects to perturb the redox state in esophageal squamous cell carcinoma (ESCC). The precise roles of these, especially their interplay, in these processes remain controversial and elusive.Methods We investigated the genetic alterations of the CKN axis and p53 in ESCC/SCCs and their interplays via bioinformatical analysis and immunoblots. Specific downstream target(s) of them were identified using bulk-RNA sequencing, RT-qPCR, immunofluorescence, and immunoblots in the immortalized esophageal cell, D3. The effects of redox balance in ESCC chemoprevention were performed using an NMBzA-induced rat ESCC model.Results NRF2 and p53DN (p53R246W) enhanced the antioxidant capacity. The pentose phosphate pathway and glutathione metabolism reprogramming were responsible for NRF2-related antioxidant capacity, with G6PD and SLC7A11 were critical targets. However, no direct interplay between NRF2 and p53 was detected. The EGFR-ERK-ETS1-SLC7A11 axis is potentially responsible for the antioxidant potency of p53R246W-D3 cells. Interestingly, the exogenous oxidant artesunate could suppress carcinogenesis in the rat ESCC model.Conclusions Abnormal NRF2 activation and the effects of p53DN appear to dysregulate the redox balance independently during ESCC carcinogenesis, suggesting that targeting the redox balance could be a promising and effective ESCC prevention and treatment strategy.