NRF2 and Aquaglyceroporins: Orchestrating Metabolic and Redox Homeostasis in Cancer Resistance

Cancer remains a primary global health challenge, characterized by high metabolic plasticity and therapy resistance. A critical factor in tumor survival is the fine-tuning of redox homeostasis, governed by the NRF2 signaling pathway. This redox balance is inevitably linked to the cellular metabolic network, where NRF2 drives the pentose phosphate pathway, NADPH production, and lipid metabolism to fuel rapid proliferation and drug detoxification. Recent evidence highlights a functional link between NRF2 and specific aquaporin (AQP) isoforms, peroxiporins and aquaglyceroporins, which facilitate the transmembrane flux of hydrogen peroxide and glycerol. By regulating the movement of these molecules, AQPs can actively contribute to both metabolic reprogramming and redox signaling. This review explores the mechanisms of NRF2 and AQP co-regulation in breast, colon, and liver cancers, illustrating their combined role in driving tumor progression and malignancy. Furthermore, we evaluate the clinical potential of targeting these pathways and discuss the utility of NRF2/AQP co-expression as a predictive biomarker for therapy outcomes. Identifying these molecular signatures offers a promising avenue for patient stratification and the development of novel therapeutic strategies to overcome tumor resistance.