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Background <p>Spinal cord injury (SCI) causes severe energy metabolism dysfunction, hindering neuronal survival and recovery. Adipose tissue-derived stromal cells (ADSCs) have neuroprotective potential, but their role in regulating neuronal energy metabolism and the underlying mechanisms remain unclear. This study aimed to investigate whether ADSCs are capable of restoring neuronal glycolysis through the FOXK1-HK2 signaling pathway, thereby replenishing the energy supply and facilitating tissue regeneration.</p> Methods <p>We employed rat and cell models of SCI to observe the effects of ADSCs on glycolytic metabolism and apoptosis. Transcriptome sequencing identified glycolysis-related differentially expressed genes. Lactate detection and Seahorse assays were used to quantify glycolytic activity. Dual-luciferase reporter assays verified the FOXK1-HK2 regulatory relationship. Cut&amp;Run assay provided direct evidence of FOXK1 binding to the HK2 promoter. Behavioral tests, histopathological staining and immunofluorescence were used to evaluate in vivo functional recovery and tissue repair. FOXK1 knockdown confirmed its role in the ADSC-mediated pathway.</p> Results <p>We found that ADSCs exerted multiple protective and regulatory effects on neurons and motor function. Specifically, they strongly inhibited neuronal oxidative stress, protected mitochondria, and promoted neuronal metabolic reprogramming. Additionally, ADSCs increased glycolytic activity and lactate production, which further contributed to promoting neuronal survival and the recovery of hindlimb motor function. Blocking TGF-β1 signaling abrogated ADSC-induced activation of the FOXK1-HK2 axis and subsequent enhancement of glycolysis, confirming TGF-β1 as a critical paracrine mediator. Through interaction with HK2, FOXK1 plays a critical role in modulating glycolysis. Dual-luciferase reporter and Cut&amp;Run assays confirmed that FOXK1 regulates the HK2 promoter, thereby increasing its transcriptional activity. The inhibition of FOXK1 expression resulted in suppressed HK2 expression, reduced glycolytic flux, and weakened the neuroprotective effects of ADSCs on SCI.</p> Conclusions <p>ADSCs are considered a potential option for SCI treatment, and their therapeutic effects are closely related to the FOXK1/HK2 axis, which mediates ADSCs’ regulation of neuronal glycolytic metabolism to exert protective and reparative functions.</p> Graphical Abstract <p></p>

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Adipose tissue-derived stromal cells enhance glycolytic metabolism in injured nerve cells via the FOXK1-HK2 axis for spinal cord injury repair

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Fang Li,
  • Hongbo Li,
  • Yanfei Jia,
  • Lanxiang Ou,
  • Yuepeng Fang,
  • Liuzhu Pan,
  • Hua Liu,
  • Bin Ning

摘要

Background

Spinal cord injury (SCI) causes severe energy metabolism dysfunction, hindering neuronal survival and recovery. Adipose tissue-derived stromal cells (ADSCs) have neuroprotective potential, but their role in regulating neuronal energy metabolism and the underlying mechanisms remain unclear. This study aimed to investigate whether ADSCs are capable of restoring neuronal glycolysis through the FOXK1-HK2 signaling pathway, thereby replenishing the energy supply and facilitating tissue regeneration.

Methods

We employed rat and cell models of SCI to observe the effects of ADSCs on glycolytic metabolism and apoptosis. Transcriptome sequencing identified glycolysis-related differentially expressed genes. Lactate detection and Seahorse assays were used to quantify glycolytic activity. Dual-luciferase reporter assays verified the FOXK1-HK2 regulatory relationship. Cut&Run assay provided direct evidence of FOXK1 binding to the HK2 promoter. Behavioral tests, histopathological staining and immunofluorescence were used to evaluate in vivo functional recovery and tissue repair. FOXK1 knockdown confirmed its role in the ADSC-mediated pathway.

Results

We found that ADSCs exerted multiple protective and regulatory effects on neurons and motor function. Specifically, they strongly inhibited neuronal oxidative stress, protected mitochondria, and promoted neuronal metabolic reprogramming. Additionally, ADSCs increased glycolytic activity and lactate production, which further contributed to promoting neuronal survival and the recovery of hindlimb motor function. Blocking TGF-β1 signaling abrogated ADSC-induced activation of the FOXK1-HK2 axis and subsequent enhancement of glycolysis, confirming TGF-β1 as a critical paracrine mediator. Through interaction with HK2, FOXK1 plays a critical role in modulating glycolysis. Dual-luciferase reporter and Cut&Run assays confirmed that FOXK1 regulates the HK2 promoter, thereby increasing its transcriptional activity. The inhibition of FOXK1 expression resulted in suppressed HK2 expression, reduced glycolytic flux, and weakened the neuroprotective effects of ADSCs on SCI.

Conclusions

ADSCs are considered a potential option for SCI treatment, and their therapeutic effects are closely related to the FOXK1/HK2 axis, which mediates ADSCs’ regulation of neuronal glycolytic metabolism to exert protective and reparative functions.

Graphical Abstract