Keap1/Nrf2 mediated Ferroptosis in Early-Life Lead Exposure-induced Cognitive Dysfunction in Mice.
TL;DR
The mechanism of Keap1/Nrf2-mediated ferroptosis in cognitive dysfunction induced by early-life Pb exposure is revealed, providing a potential therapeutic strategy targeting this pathway to alleviate Pb exposure-associated neurodegenerative lesions.
Abstract
Background
Early-life lead (Pb) exposure has been confirmed to cause long-term cognitive impairment, but the mechanisms of its programmed cell death remain incompletely elucidated. This study aims to investigate the key role of Nrf2-mediated ferroptosis in early-life Pb exposure-induced cognitive impairment in mice.
Methods
By employing both in vivo and in vitro approaches, we explored the involvement of Keap1/Nrf2-mediated ferroptosis in early-life Pb exposure-induced cognitive impairment.
Results
Our findings showed that early-life Pb exposure induced ferroptosis by upregulating hippocampal Keap1 expression and inhibiting the Nrf2 pathway and its downstream antioxidant proteins (GPX4, SLC7A11, and SLC3A2), and altering the expression of iron metabolism-related proteins (downregulating FTH1/FTL and upregulating DMT1). This process led to ferroptosis, as evidenced by elevated levels of the lipid peroxidation product MDA and reduced glutathione peroxidase activity. Furthermore, this process was accompanied by upregulation of the neurodegeneration-related protein APP in hippocampal tissues, which ultimately resulted in neurodegenerative lesions.
Conclusion
This study reveals the mechanism of Keap1/Nrf2-mediated ferroptosis in cognitive dysfunction induced by early-life Pb exposure, providing a potential therapeutic strategy targeting this pathway to alleviate Pb exposure-associated neurodegenerative lesions.