NRF2 signalling in environmental metal and metalloid neurotoxicity: distinguishing stress responses from functional neuroprotection

Exposure to toxic metals and metalloids is an important public health concern because they can damage the nervous system and impair cognitive and motor function. Oxidative stress, disturbed glutathione balance, mitochondrial dysfunction and neuroinflammation are common features of this damage. Nuclear factor erythroid 2-related factor 2 (NRF2) regulates proteins that help cells maintain redox balance and withstand toxic stress. Increased NRF2 expression after metal exposure is therefore often interpreted as evidence of protection. However, expression alone does not show that the pathway is working effectively. Functional activation requires NRF2 nuclear translocation, binding to antioxidant-response elements, induction of target genes and improvement in redox or mitochondrial function. This review critically examines human, animal and cellular evidence concerning NRF2 responses to cadmium, lead, mercury, arsenic and manganese. It considers how dose, duration, brain region and cell type shape these responses and evaluates compounds intended to modify NRF2 signalling. It assesses whether NRF2 dependence was demonstrated using genetic deletion, knockdown, pharmacological inhibition or rescue rather than inferred from expression changes. Current evidence supports NRF2 as an important but context-dependent defence mechanism. However, causal evidence remains uneven, human data are limited and many proposed activators have effects beyond NRF2. Future studies should use environmentally relevant exposures and directly measure pathway activity, mitochondrial function and neurological outcomes. This is necessary to determine whether NRF2 modulation can provide safe and meaningful protection against environmental neurotoxicity.