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Interference with HMGB1 Inhibits Neuronal Ferroptosis Following Spinal Cord Injury through Targeting ACSL4
Zhiwu Wu1, Qinglin Zhong1, Tao Li1
1Department of Neurosurgery, Ganzhou People's Hospital, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, 341000, China.
Neurochemical Research
|May 28, 2026
Summary
High-mobility group box 1 (HMGB1) regulates neuronal ferroptosis after spinal cord injury (SCI) by suppressing acyl-CoA synthetase long-chain family member 4 (ACSL4). Inhibiting HMGB1 reduces iron deposition and cell death in SCI rats.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Spinal cord injury (SCI) can lead to significant neuronal damage.
- Neuronal ferroptosis, an iron-dependent cell death pathway, contributes to secondary injury after SCI.
- The specific regulatory mechanisms of ferroptosis in SCI remain incompletely understood.
Purpose of the Study:
- To investigate the role of High-mobility group box 1 (HMGB1) in regulating neuronal ferroptosis following SCI.
- To elucidate the underlying molecular mechanisms, particularly the interaction between HMGB1 and acyl-CoA synthetase long-chain family member 4 (ACSL4).
- To evaluate the therapeutic potential of targeting HMGB1 in SCI.
Main Methods:
- SCI rat models were established, and spinal cord tissues were analyzed for iron deposition, lipid peroxidation markers (MDA), antioxidant levels (GSH), and key protein expressions (HMGB1, ACSL4, SLC7A11, GPX4) at various time points.
- An in vitro neuronal ferroptosis model was created using lentiviral vectors for HMGB1 interference and ACSL4 overexpression to assess cellular responses.
- SCI rats were treated with the HMGB1 inhibitor glycyrrhizic acid (GA) to evaluate its therapeutic effects on SCI-induced ferroptosis.
Main Results:
- SCI induced time-dependent increases in iron deposition, MDA, HMGB1, and ACSL4, while decreasing GSH, GPX4, and SLC7A11.
- In vitro studies showed that HMGB1 interference attenuated neuronal ferroptosis by suppressing ACSL4 expression.
- Administration of GA to SCI rats significantly reduced iron deposition and MDA levels, while restoring GSH, GPX4, and SLC7A11, and decreasing HMGB1 and ACSL4 expression.
Conclusions:
- HMGB1 plays a critical role in promoting neuronal ferroptosis after SCI, primarily through the upregulation of ACSL4.
- Targeting HMGB1 with inhibitors like GA demonstrates a promising therapeutic strategy for mitigating neuronal damage and ferroptosis in SCI.
- Understanding the HMGB1-ACSL4 axis provides new insights into the pathogenesis of SCI and potential therapeutic targets.
