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The Syvn1 inhibits neuronal cell ferroptosis by activating Stat3/Gpx4 axis in rat with spinal cord injury
Shining Xiao1,2,3, Yu Zhang1,2,3, Shijiang Wang1,2,3
1Department of Orthopedics, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People's Republic of China.
Abstract:
Spinal cord injury (SCI) leads to secondary neuronal death, which severely impedes recovery of motor function. Therefore, prevention of neuronal cell death after SCI is an important strategy. Ferroptosis, a new form of cell death discovered in recent years, has been shown to be involved in the regulation of SCI. However, the role and potential mechanisms of ferroptosis in secondary SCI are not fully understood. In this study, we report that the E3 ubiquitin ligase Syvn1 suppresses ferroptosis and promotes functional recovery from SCI in vitro and in vivo. Mechanistically, screened with bioinformatics, immunoprecipitation, and mass spectrometry, we identified Stat3, a transcription factor that induces the expression of the ferroptosis inhibitor Gpx4, as a substrate of Syvn1. Furthermore, we identified neurons as the primary cellular source of Syvn1 signalling. Moreover, we determined the binding domains of Syvn1 and Stat3 in HEK 293 T cells using full-length proteins and a series of truncated Flag-tagged and Myc-tagged fragments. Furthermore, we created the cell and animal models with silencing or overexpression of Syvn1 and Stat3 and found that Syvn1 inhibits neuronal ferroptosis by stabilizing Stat3, which subsequently activates the ferroptosis regulator Gpx4 in SCI. In summary, the Syvn1-mediated Stat3/Gpx4 signalling axis attenuates neuronal ferroptosis, reduces neuronal death, and promotes SCI repair. Therefore, our findings provide potential new targets and intervention strategies for the treatment of SCI.
Insights
The E3 ubiquitin ligase Syvn1 prevents ferroptosis, a cell death pathway, in neurons after spinal cord injury (SCI). This mechanism, involving Stat3 and Gpx4, promotes functional recovery following SCI.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Spinal cord injury (SCI) causes secondary neuronal death, hindering motor function recovery.
- Ferroptosis, a distinct cell death form, is implicated in SCI, but its precise role and mechanisms remain unclear.
- Preventing neuronal death is crucial for improving SCI outcomes.
Purpose of the Study:
- To investigate the role of E3 ubiquitin ligase Syvn1 in ferroptosis following SCI.
- To elucidate the molecular mechanisms by which Syvn1 influences neuronal cell death and functional recovery.
- To identify potential therapeutic targets for SCI treatment.
Main Methods:
- Bioinformatics screening, immunoprecipitation, and mass spectrometry to identify Syvn1 substrates.
- HEK 293 T cell experiments to determine binding domains between Syvn1 and Stat3.
- In vitro and in vivo cell and animal models with Syvn1 and Stat3 manipulation (silencing/overexpression).
Main Results:
- Syvn1 was identified as a suppressor of ferroptosis, promoting functional recovery in SCI models.
- Stat3 was identified as a substrate of Syvn1, and it induces the expression of the ferroptosis inhibitor Gpx4.
- Syvn1 stabilizes Stat3, which then activates Gpx4, thereby inhibiting neuronal ferroptosis and reducing cell death in SCI.
- Neurons were confirmed as the primary source of Syvn1 signaling.
Conclusions:
- The Syvn1-Stat3/Gpx4 signaling axis effectively mitigates neuronal ferroptosis after SCI.
- Targeting this pathway offers a promising strategy for reducing neuronal death and promoting repair in spinal cord injuries.
- Syvn1 represents a potential therapeutic target for enhancing recovery from SCI.
