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Background <p>Hypertrophic scar (HS) is a fibroproliferative skin disorder characterized by excessive fibroblast proliferation and collagen overproduction during aberrant wound healing. Although hypoxia is a well-recognized driver of HS formation, the molecular mechanisms linking hypoxic signaling to fibroblast activation remain incompletely understood.</p> Methods <p>In this study, the expression of hypoxia-inducible factor 1α (HIF-1α), neuronal regeneration–related protein (NREP), and phosphorylated small mother against decapentaplegic family member 2/3 (p-Smad2/3) was examined in HS and matched normal tissues from patients. Hypertrophic scar fibroblasts (HSFBs) were cultured under hypoxic or normoxic conditions, followed by genetic manipulation of HIF-1α or NREP to assess their effects on fibroblast proliferation and collagen synthesis. The direct transcriptional regulation of NREP by HIF-1α was confirmed using dual-luciferase reporter and ChIP assays.</p> Results <p>Compared with normal tissues, HS tissues exhibited markedly elevated expression of HIF-1α, NREP, and phosphorylated Smad2/3. Hypoxia significantly increased HIF-1α and NREP levels in HSFBs, promoting fibroblast proliferation and collagen deposition, whereas knockdown of either HIF-1α or NREP abrogated these effects. Mechanistically, HIF-1α directly bound to the NREP promoter to enhance its transcription, and NREP overexpression partially rescued the suppressive effects of HIF-1α knockdown. Furthermore, HIF-1α-induced NREP upregulation activated the TGF-β1/Smad signaling cascade, while inhibition of this cascade counteracted the effect of NREP overexpression on the changes caused by HIF-1α silencing.</p> Conclusion <p>Our findings identify a novel HIF-1α/NREP/TGF-β1–Smad axis that drives fibroblast hyperproliferation and excessive collagen accumulation in HS. Targeting this signaling pathway may offer a promising therapeutic strategy for preventing or treating HS formation.</p> Graphical Abstract <p></p>

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HIF-1α/NREP axis promotes hypertrophic scar fibroblast proliferation and collagen deposition via activation of the TGF-β1/Smad pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Baiye Chen,
  • Chaofan Lin,
  • Xueming Wang,
  • Weiwen Zhu,
  • Jiaqi Zhang,
  • Liu Chen

摘要

Background

Hypertrophic scar (HS) is a fibroproliferative skin disorder characterized by excessive fibroblast proliferation and collagen overproduction during aberrant wound healing. Although hypoxia is a well-recognized driver of HS formation, the molecular mechanisms linking hypoxic signaling to fibroblast activation remain incompletely understood.

Methods

In this study, the expression of hypoxia-inducible factor 1α (HIF-1α), neuronal regeneration–related protein (NREP), and phosphorylated small mother against decapentaplegic family member 2/3 (p-Smad2/3) was examined in HS and matched normal tissues from patients. Hypertrophic scar fibroblasts (HSFBs) were cultured under hypoxic or normoxic conditions, followed by genetic manipulation of HIF-1α or NREP to assess their effects on fibroblast proliferation and collagen synthesis. The direct transcriptional regulation of NREP by HIF-1α was confirmed using dual-luciferase reporter and ChIP assays.

Results

Compared with normal tissues, HS tissues exhibited markedly elevated expression of HIF-1α, NREP, and phosphorylated Smad2/3. Hypoxia significantly increased HIF-1α and NREP levels in HSFBs, promoting fibroblast proliferation and collagen deposition, whereas knockdown of either HIF-1α or NREP abrogated these effects. Mechanistically, HIF-1α directly bound to the NREP promoter to enhance its transcription, and NREP overexpression partially rescued the suppressive effects of HIF-1α knockdown. Furthermore, HIF-1α-induced NREP upregulation activated the TGF-β1/Smad signaling cascade, while inhibition of this cascade counteracted the effect of NREP overexpression on the changes caused by HIF-1α silencing.

Conclusion

Our findings identify a novel HIF-1α/NREP/TGF-β1–Smad axis that drives fibroblast hyperproliferation and excessive collagen accumulation in HS. Targeting this signaling pathway may offer a promising therapeutic strategy for preventing or treating HS formation.

Graphical Abstract