ArticleBiology direct2026
HIF-1α/NREP axis promotes hypertrophic scar fibroblast proliferation and collagen deposition via activation of the TGF-β1/Smad pathway.
Article in Biology direct, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
1 citing paper in PubMed.
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHypertrophic 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.
methodsIn 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.
resultsCompared 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.
conclusionOur 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.
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