Hyperoside accelerates myelin debris clearance by inhibiting signal transducer and activator of transcription 3 phosphorylation in peripheral nerve injury

  • Phytomedicine. 2026 Jul:156:158214. doi: 10.1016/j.phymed.2026.158214.
Bang Su  1 ,  Nan Wang  1 ,  Xiaoping Xie  2 ,  Dongxu Huang  1 ,  Xin Yu  1 ,  Zhenmin Jiang  1 ,  Di Wang  3 ,  Yajing Gong  1 ,  Ruolin Jia  4 ,  Laijin Lu  1 ,  Xiguang Sun  5
Affiliations
  • 1. Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun 130031, PR China; Jilin Province Key Laboratory on Tissue Repair, Reconstruction and Regeneration, The First Hospital of Jilin University, Changchun 130031, PR China.
  • 2. Department of Trauma Orthopedics, Orthopedics Center, The First Hospital of Jilin University, Changchun 130031, PR China.
  • 3. Jilin Province Key Laboratory on Tissue Repair, Reconstruction and Regeneration, The First Hospital of Jilin University, Changchun 130031, PR China; Phase I Clinical Trial Center, The First Hospital of Jilin University, Changchun 130031, PR China.
  • 4. Jilin Province Key Laboratory on Tissue Repair, Reconstruction and Regeneration, The First Hospital of Jilin University, Changchun 130031, PR China; Department of Reproductive Medicine, The First Hospital of Jilin University, Changchun 130031, PR China.
  • 5. Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun 130031, PR China; Jilin Province Key Laboratory on Tissue Repair, Reconstruction and Regeneration, The First Hospital of Jilin University, Changchun 130031, PR China. Electronic address: [email protected].
PMID: 42025010 DOI: 10.1016/j.phymed.2026.158214
Abstract

Background: Neuroinflammation resulting from myelin debris impedes axonal regeneration. Pharmacological modulation of myelin clearance and inflammatory responses is a potential strategy to enhance nerve regeneration. Hyperoside, a flavonoid with established anti-inflammatory and neuroprotective properties, has not been explored in peripheral nerve injury or in the context of myelin clearance.

Purpose: This study aims to investigate the effects and underlying mechanisms of hyperoside in promoting nerve regeneration.

Methods: An in vitro phagocytosis model was established in RAW264.7 macrophages with purified myelin debris. Cells were treated with hyperoside (10, 15, 30 μM). Direct hyperoside targets were identified through molecular docking and small-molecule interaction assays. Gain- and loss-of-function experiments using LPS and Stattic were performed to validate the involvement of the STAT3/ADAM17/TREM2 signaling axis. In vivo sciatic nerve crush injury models were used to examine the relationship among TREM2-mediated myelin clearance, sciatic nerve regeneration, and functional recovery.

Results: Hyperoside dose-dependently inhibited pro-inflammatory gene expression and apoptosis-related proteins. Mechanistically, hyperoside bound STAT3 and inhibited its phosphorylation, thereby downregulating ADAM17 and preserving TREM2-mediated myelin phagocytosis. In the sciatic nerve crush injury model, hyperoside exerted neuroprotective effects, accelerated degenerated myelin clearance, promoted nerve regeneration, and reduced muscle atrophy. Trem2 silencing impaired myelin clearance and nerve regeneration.

Conclusion: These findings highlight hyperoside as a promising therapeutic candidate for peripheral nerve injury. By targeting the STAT3/ADAM17/TREM2 signaling axis to enhance myelin clearance, hyperoside promotes structural and functional nerve regeneration in a rodent nerve injury model.

Keywords
Hyperoside; Macrophage polarization; Myelin clearance; Peripheral nerve regeneration; TREM2.
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