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CNS Neuroscience & Therapeutics

CNS Neuroscience & Therapeutics

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The Role of P62/Nrf2/Keap1 Signaling Pathway in Lead-Induced Neurological Dysfunction

Published:5 September 2025 DOI: 10.1111/cns.70566
Dongjie Peng, Peiqi Wei, Zhenning Li, Ruokun Wei, Huishuai Li, Shaojun Li

Abstract

Background

Lead (Pb) exposure is recognized for its contribution to the development of neurodegenerative diseases. However, the precise mechanisms underlying Pb-induced neurological dysfunction remain elusive. This study aimed to investigate the role of oxidative stress and the autophagy-related P62/kelch like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in neuronal impairment caused by Pb.

Methods

By employing both in vivo and in vitro approaches, we explored the involvement of the P62/Nrf2/Keap1 pathway in Pb-induced neurotoxicity.

Results

Our findings demonstrated that Pb exposure triggers excessive production of reactive oxygen species (ROS), upregulates Keap1 protein expressions, promotes Nrf2 degradation, and inhibits expression of antioxidant proteins such as heme Oxygenase-1 (HO-1) and glutathione peroxidase (GPx), resulting in oxidative damage in neurons. Furthermore, we observed that the autophagy protein P62 disrupts the normal autophagy process by interacting with the Nrf2/Keap1 axis, leading to an accumulation of Tau, a protein associated with Alzheimer's disease (AD), ultimately resulting in neurodegeneration. However, treatment with the antioxidant N-acetylcysteine, Nrf2 activator Artemisitene, and autophagy activator Rapamycin attenuated these detrimental changes.

Conclusion

The P62/Nrf2/Keap1 pathway mediates Pb-induced neuronal dysfunction and highlights its potential as a therapeutic target for mitigating the neurodegenerative effects associated with Pb exposure.

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