Neurospine.  2025 Mar;22(1):157-172. 10.14245/ns.2448878.439.

Extracellular Ubiquitin Enhances Autophagy and Inhibits Mitochondrial Apoptosis Pathway to Protect Neurons Against Spinal Cord Ischemic Injury via CXCR4

• Feng H
• Chen D
• Chen H
• Wu D
• Wang D
• Yu Z
• Zhou L
• Wang Z
• Liu W

• KMID: 2566051
• DOI: http://doi.org/10.14245/ns.2448878.439

Abstract

Objective
Neuronal apoptosis is considered to be a critical process in spinal cord injury (SCI). Despite growing evidence of the antiapoptotic, anti-inflammatory, and modulation of ischemic injury tolerance effects of extracellular ubiquitin (eUb), existing studies have paid less attention to the impact of eUb in neurological injury disorders, particularly in SCI. This study aimed to investigate whether eUb can play a protective role in neurons, both in vitro and in vivo, and explores the underlying mechanisms.
Methods
By utilizing an oxygen glucose deprivation cellular model and a SCI rat model, we firstly investigated the therapeutic effects of eUb on SCI and further explored its effects on neuronal autophagy and mitochondria-dependent apoptosis-related indicators, as well as the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanical target of rapamycin (mTOR) signaling pathway.
Results
In the SCI models both in vivo and in vitro, early intervention with eUb enhanced neuronal autophagy and inhibited mitochondrial apoptotic pathways, significantly mitigating SCI. Further studies had shown that this protective effect of eUb was mediated through its receptor, CXC chemokine receptor type 4 (CXCR4). Additionally, eUb-enhanced autophagy and antiapoptotic effects were possibly associated with inhibiting the PI3K/Akt/mTOR pathway.
Conclusion
In summary, the study demonstrates that early eUb intervention can enhance autophagy and inhibit mitochondrial apoptotic pathways via CXCR4, protecting neurons and promoting SCI repair.

Keyword

Spinal cord injury; Extracellular ubiquitin; CXCR4; Autophagy; Mitochondrial apoptosis pathway