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Updated: Jul 10, 2026

An Optimized O9-1/Hydrogel System for Studying Mechanical Signals in Neural Crest Cells
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Substrate stiffness regulates HIF-1α signalling via β1-integrin/myosin-2/NF-κB axis.

Ander Bastida Urkiza1,2, Ernesto Cortes3, Chongguang Jin2

  • 1Department of Neuroscience and Biomedical Sciences, Universidad Carlos III de Madrid, Madrid, 28903, Spain.

Journal of Translational Medicine
|July 9, 2026
PubMed
Summary
This summary is machine-generated.

Matrix stiffness activates Hypoxia-Inducible Factor 1-alpha (HIF-1α) under normal oxygen conditions via mechanical signaling. This pathway involves NF-κB and can be pharmacologically targeted.

Keywords:
Alpha subunitCytoskeletal tensionHypoxia-inducible factorSubstrate stiffnessTranscriptional regulation

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Area of Science:

  • Cell Biology
  • Mechanobiology
  • Molecular Biology

Background:

  • Hypoxia-Inducible Factor 1-alpha (HIF-1α) is typically activated by low oxygen, regulating key cellular processes.
  • Activation of HIF-1α under normoxia and its response to mechanical stimuli are not fully understood.
  • Investigating mechanical cues in modulating HIF-1α activation and the role of the NF-κB pathway is crucial.

Purpose of the Study:

  • To investigate how mechanical stimuli, specifically matrix stiffness, modulate HIF-1α activation under normoxia.
  • To elucidate the role of the NF-κB pathway in mediating this mechanosensitive regulation.
  • To explore potential pharmacological targeting of this pathway.

Main Methods:

  • Primary human lung fibroblasts (PSCs) cultured on hydrogels of varying stiffness.
  • Analysis of HIF-1α nuclear translocation and functional activation.
  • Investigation of mechanosensitive pathways including β1 integrin, RhoA/MLC-2, and NF-κB signaling.
  • Pharmacological modulation using a GPER agonist.

Main Results:

  • Substrate stiffness induced significant nuclear translocation and functional activation of HIF-1α under normoxia.
  • This activation was dependent on β1 integrin-mediated actomyosin contractility and NF-κB signaling.
  • NF-κB activation was essential for functional HIF-1α activation, linking mechanical stimuli to inflammatory and hypoxia pathways.
  • Pharmacological targeting via a GPER agonist modulated both NF-κB and HIF-1α activation by regulating actomyosin tension.

Conclusions:

  • Substrate stiffness activates HIF-1α under normoxia through a β1 integrin/MLC-2/NF-κB signaling axis.
  • This study reveals a novel mechanosensitive pathway linking matrix stiffness to HIF-1α signaling.
  • The identified pathway represents a potential target for pharmacological intervention.