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Single-Cell RNA Sequencing and Network Pharmacology Reveal the Potential Role of Oxidative Phosphorylation

Jie-Jie Niu1, Long Wang2, Jia-Chen Qi1

  • 1Department of Pain, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.

The Journal of Gene Medicine
|January 29, 2026
PubMed
Abstract

Insights

Chronic tendon injuries involve impaired energy metabolism due to reduced oxidative phosphorylation (OXPHOS). Valproic acid shows promise for treating these conditions by restoring OXPHOS and inhibiting cell death.

Area of Science:

  • Mitochondrial biology
  • Cellular metabolism
  • Regenerative medicine

Background:

  • Chronic tendon injuries present a significant clinical challenge with limited effective treatments.
  • These injuries are characterized by persistent pain, reduced flexibility, and impaired function.
  • Oxidative phosphorylation (OXPHOS) plays a critical role in maintaining tendon homeostasis.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying chronic tendon injuries.
  • To identify key cellular pathways and potential therapeutic targets.
  • To evaluate the role of OXPHOS in tendon health and disease.

Main Methods:

  • Utilized bulk and single-cell RNA sequencing (scRNA-seq) to analyze cell heterogeneity in lesional and non-lesional tendons.
  • Examined tenocytes, vascular endothelial cells, tendon-derived stem cells, adipocytes, and neurons.
  • Investigated the effects of bisphenol A and valproic acid on OXPHOS-related genes.

Main Results:

  • Significant downregulation of key OXPHOS-related genes was observed in lesional tendons across multiple cell types.
  • Reduced OXPHOS activity correlates with increased necroptosis in chronic tendon injuries.
  • Bisphenol A and valproic acid were identified as activators of OXPHOS-related genes.

Conclusions:

  • OXPHOS is crucial for maintaining tendon homeostasis and represents a potential therapeutic target.
  • Valproic acid activates OXPHOS and inhibits necroptosis in vitro, suggesting its potential as a therapeutic agent for chronic tendon injuries.
  • Restoring OXPHOS activity may offer a promising strategy for enhancing tendon healing.
Keywords:
ScRNA‐seqbulk‐seqchronic tendon injuriesoxidative phosphorylation

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