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20-Deoxyingenol alleviates ferroptosis by activating transcription factor EB in spinal cord injury
Pan Wang1,2,3, Tangyue Li4, Xin Zhang1,3
1Department of Neurosurgery, Cheeloo College of Medicine, Qilu Hospital.
Background:
Spinal cord injury (SCI) lacks effective treatments. Ferroptosis contributes to SCI pathology. We investigated the therapeutic potential of 20-deoxyingenol (20-DOI), a natural diterpene, focusing on its role in inhibiting ferroptosis.
Methods:
We used ventral spinal cord 4.1 motor neurons in vitro, challenged with H2O2 or erastin. Assessments included cell viability, proliferation, autophagy, lysosomal function, and ferroptosis. Transcription factor EB (TFEB) knockdown validated its involvement. In vivo, a mouse SCI model assessed functional recovery (Basso mouse scale score), tissue damage, and ferroptosis markers.
Results:
20-DOI restored cell viability and proliferation, enhanced autophagy and lysosomal activity. It suppressed ferroptosis, reducing lipid peroxidation and reactive oxygen species, and preserving mitochondrial function. These benefits required TFEB; its knockdown abolished the protection and reduced NRF2/GPX4 levels. In mice, 20-DOI improved motor function, preserved neurons, and attenuated ferroptosis.
Conclusion:
20-DOI promotes recovery after SCI by activating TFEB to inhibit ferroptosis. Our work identifies TFEB as a key target and 20-DOI as a promising therapeutic agent.
Insights
20-deoxyingenol (20-DOI) shows therapeutic potential for spinal cord injury (SCI) by inhibiting ferroptosis. This natural compound activates Transcription Factor EB (TFEB), improving motor function and neuronal survival in SCI models.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Spinal cord injury (SCI) remains a significant clinical challenge with limited effective treatments.
- Ferroptosis, a form of regulated cell death, plays a critical role in the secondary injury phase following SCI.
- Investigating novel therapeutic strategies targeting ferroptosis is crucial for improving SCI outcomes.
Purpose of the Study:
- To evaluate the therapeutic potential of 20-deoxyingenol (20-DOI), a natural diterpene, in the context of spinal cord injury.
- To elucidate the mechanism by which 20-DOI exerts its protective effects, particularly its role in inhibiting ferroptosis.
- To assess the involvement of Transcription Factor EB (TFEB) in mediating the neuroprotective effects of 20-DOI.
Main Methods:
- In vitro studies utilized ventral spinal cord 4.1 motor neurons challenged with oxidative stress or ferroptosis inducers.
- In vivo experiments employed a mouse model of spinal cord injury to assess functional recovery and neuropathology.
- Key cellular processes including viability, proliferation, autophagy, lysosomal function, and ferroptosis markers were analyzed, alongside TFEB manipulation.
Main Results:
- 20-DOI treatment significantly restored motor neuron viability and proliferation in vitro.
- 20-DOI suppressed ferroptosis by reducing lipid peroxidation and reactive oxygen species, while preserving mitochondrial function.
- In vivo, 20-DOI administration improved motor function, preserved neuronal integrity, and attenuated ferroptosis markers in a mouse SCI model, dependent on TFEB activation.
Conclusions:
- 20-deoxyingenol (20-DOI) demonstrates significant neuroprotective effects in spinal cord injury models.
- The therapeutic benefits of 20-DOI are mediated through the activation of Transcription Factor EB (TFEB), leading to the inhibition of ferroptosis.
- 20-DOI represents a promising therapeutic candidate for spinal cord injury, with TFEB as a key molecular target.