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LXRα/SCD1-Mediated Endoplasmic Reticulum-Mitochondria Crosstalk in Inhibiting Neuronal Ferroptosis after Spinal Cord
Pan Jiang1,2,3,4, Yiqian Luo1,3,4, Daoqiang Huang1,3,4
1Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
Research (Washington, D.C.)
|June 19, 2026
Summary
Spinal cord injury (SCI) triggers ferroptosis via excessive endoplasmic reticulum-mitochondria contact sites (ERMCSs). Activating the LXRα-SCD1 pathway reduces ERMCSs, inhibiting ferroptosis and improving recovery after SCI.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Spinal cord injury (SCI) leads to significant neuronal death, with ferroptosis playing a key role.
- Lipid transport at endoplasmic reticulum-mitochondria contact sites (ERMCSs) influences ferroptosis, but neuron-specific regulation is unclear.
Purpose of the Study:
- To elucidate the mechanisms regulating ferroptosis in neurons after SCI.
- To identify therapeutic targets for mitigating neuronal loss and improving functional recovery.
Main Methods:
- Systematic screening to identify key enzymes involved in neuronal ferroptosis.
- Investigating the role of stearoyl-CoA desaturase 1 (SCD1) and liver X receptor alpha (LXRα) in SCI models.
- Utilizing in vivo (murine SCI models) and in vitro (erastin treatment) approaches.
- Employing adeno-associated virus (AAV)-mediated gene delivery and pharmacological agonists.
Main Results:
- Neuronal ferroptosis in SCI is associated with excessive ERMCS formation.
- SCD1 deficiency drives ERMCS expansion, lipid peroxidation, and ferroptosis; SCD1 overexpression reverses these effects.
- LXRα directly activates SCD1 transcription; LXRα activation inhibits ferroptosis by upregulating SCD1.
- LXRα agonist treatment and neuronal SCD1 overexpression in murine SCI models reduced lesion size, preserved neurons, and improved functional recovery.
Conclusions:
- The LXRα-SCD1 axis is a novel pathway regulating ERMCS-dependent lipid exchange and neuronal ferroptosis.
- Targeting the LXRα-SCD1 pathway offers a promising therapeutic strategy for central nervous system trauma.
- Modulating lipid metabolism at ERMCSs presents a viable approach to reduce neuronal loss and enhance recovery after SCI.