2. Academic Validation
  3. Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice

Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice

  • Br J Pharmacol. 2025 Jul 21. doi: 10.1111/bph.70122.
Rongjie Liu 1 2 3,  Yituo Chen 4,  Haosheng Huang 1 2 3,  Xiang Li 1 2 3,  Junlei Lv 1 2 3,  Liting Jiang 1 2 3,  Hongyi Jiang 1 2 3,  Chenyu Wu 1 2 3 5,  Weikai Chen 1 2 3,  Hongwei Xu 1 2 3,  Zhefan Zhu 1 2 3,  Haoxu Cai 1 2 3,  Jian Xiao 5,  Lihui Yin 6,  Wenfei Ni 1 2 3
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2 Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, China.
  • 3 The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, China.
  • 4 Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 6 Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
PMID: 40692165 DOI: 10.1111/bph.70122
Abstract

Background and purpose: Lysosomal membrane permeabilization (LMP) is exacerbated following spinal cord injury (SCI), leading to increased neuronal cell death. Ubiquitination may affect LMP by regulating the stability and functionality of lysosomal membranes. Semax, a synthetic heptapeptide, comprising the ACTH (4-7) fragment and a C-terminal Pro-Gly-Pro tripeptide, exhibits neuroprotective properties and improves cognitive function. Given the key roles of LMP and ubiquitination in SCI pathophysiology, this study investigated how Semax could modulate these pathways to affect functional recovery following SCI.

Experimental approach: An SCI mouse model was generated by impacting the spinal cord of female C57BL/6 mice at T9-T10. Functional recovery in SCI mice was evaluated using histochemical methods, along with footprint analysis, Basso scores and inclined plane tests. Marker levels and distributions in the SCI model and in the PC12 cell neuroinflammation model were analysed using immunofluorescence, Western blot, RT-qPCR and transmission electron microscopy. RNA Sequencing, network pharmacology and molecular docking were used to identify possible molecular targets of Semax.

Key results: Semax improved SCI functional recovery and inhibited LMP-related Pyroptosis in SCI mice and neuroinflammation models, by decreasing oxidative stress. RNA-seq and Other analyses found that Semax regulated the ubiquitin specific protease USP18. USP18 knockdown confirmed Semax's role in SCI recovery. Network pharmacology and docking revealed the μ-opioid receptor as a Semax target.

Conclusion and implications: Semax promoted SCI functional recovery by targeting μ-opioid receptors, which regulated USP18 and, subsequently, deubiquitination of the fat mass and obesity-associated protein (FTO), suggesting its potential for SCI treatment.

Keywords

Semax; USP18; lysosomal membrane permeabilization; oxidative stress; pyroptosis; spinal cord injury.

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