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FGF21 attenuates traumatic brain injury-induced ferroptosis via activation of the Nrf2/GPX4 pathway
Yunfeng Xu1, Andong Zhang2, Guangning Zhang1
1Department of Neurosurgery, The Affiliated Hospital of Jiaxing University, Jiaxing, China.
Background:
Traumatic brain injury (TBI) triggers secondary neuronal damage via oxidative stress and ferroptosis. This study examines the neuroprotective effect of fibroblast growth factor 21 (FGF21) in TBI and its regulation of the Nrf2/GPX4 signaling pathway.
Methods:
TBI was induced in C57BL/6 mice using a controlled cortical impact model. Post-injury, mice received low- or high-dose recombinant FGF21, with or without the Nrf2 inhibitor ML385. Neurological function was evaluated using Garcia scoring and the Morris Water Maze. Oxidative stress, cerebral edema, and iron deposition were measured. In vitro, primary rat cortical neurons were treated with erastin (a ferroptosis inducer) ± FGF21 or ferrostatin-1. Neuronal viability, morphology, and Nrf2/GPX4 expression were analyzed by immunofluorescence, Western blotting, and RT-qPCR.
Results:
FGF21 significantly improved neurological outcomes in TBI mice, reduced edema and iron deposition, and attenuated oxidative stress. In vitro, FGF21 preserved neuronal structure and viability under ferroptotic conditions. Mechanistically, it enhanced Nrf2 nuclear translocation and upregulated GPX4. These effects were abolished by Nrf2 inhibition, confirming pathway involvement.
Conclusion:
FGF21 protects against TBI-induced secondary injury by suppressing ferroptosis and oxidative stress via Nrf2/GPX4 activation, highlighting its potential as a therapeutic strategy for TBI.
Insights
Fibroblast growth factor 21 (FGF21) offers neuroprotection against traumatic brain injury (TBI) by reducing oxidative stress and ferroptosis. FGF21 activates the Nrf2/GPX4 pathway, showing therapeutic potential for TBI treatment.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Traumatic brain injury (TBI) causes secondary neuronal damage through oxidative stress and ferroptosis.
- Fibroblast growth factor 21 (FGF21) is investigated for its potential neuroprotective effects in TBI.
- The study explores FGF21's role in regulating the Nrf2/GPX4 signaling pathway.
Purpose of the Study:
- To evaluate the neuroprotective effect of FGF21 in a mouse model of TBI.
- To investigate the mechanism by which FGF21 modulates the Nrf2/GPX4 signaling pathway.
- To assess FGF21's impact on oxidative stress, ferroptosis, and neuronal survival post-TBI.
Main Methods:
- A controlled cortical impact model was used to induce TBI in C57BL/6 mice.
- Mice received FGF21 treatment, with or without Nrf2 inhibition (ML385).
- In vitro studies utilized primary rat cortical neurons treated with ferroptosis inducers and FGF21.
Main Results:
- FGF21 administration significantly improved neurological function, reduced cerebral edema, and decreased iron deposition in TBI mice.
- In vitro, FGF21 protected neurons from ferroptosis-induced cell death and preserved cellular morphology.
- FGF21 enhanced Nrf2 nuclear translocation and upregulated GPX4 expression, effects blocked by Nrf2 inhibition.
Conclusions:
- FGF21 demonstrates significant neuroprotective properties against TBI-induced secondary injury.
- The mechanism involves the suppression of ferroptosis and oxidative stress through Nrf2/GPX4 pathway activation.
- FGF21 presents a promising therapeutic candidate for managing TBI.
