Enhancing collagen biosynthesis in mammalian cells through hypoxia-mimetic prolyl hydroxylase inhibition
Abstract
Collagen, the most abundant protein in the extracellular matrix of mammalian cells, is a key biomaterial in various biotechnological and therapeutic applications, such as tissue engineering and regeneration, cosmetics, and cultivated meat. Despite the increasing demand for culture-based collagen, it is still mainly produced from animal connective tissues. A recent study has shown that under hypoxia, activation of the hypoxia-inducible factor (HIF) leads to enhanced type I collagen biosynthesis. However, under normal oxygen conditions, HIF activity is downregulated by the HIF-prolyl hydroxylase (PHD) enzyme. Based on these previous findings, we hypothesized that inhibiting PHD activity by exogenous modulators could mimic hypoxia, leading to elevated HIF transcriptional activity and enhancing collagen biosynthesis under normoxia. Our study demonstrates that pharmacological PHD inhibition using a set of small molecules targeting their 2-oxoglutarate (2-OG)-dependent activity is associated with enhanced HIF activity, upregulation of key-collagen modifying enzymes, including collagen prolyl 4-hydroxylases and lysyl hydroxylases, accompanied by a 10- to 29-fold increase in collagen type I fluorescence intensity in NIH/3T3 embryonic mouse fibroblast cells. These findings show that targeting PHD can effectively enhance collagen production in mammalian cells, suggesting that the modulation of intracellular key protein signaling pathways presents a promising strategy for enhancing the production of culture-based collagen.
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BibTeX
@article{shahar2026enhancing,
title = {{Enhancing collagen biosynthesis in mammalian cells through hypoxia-mimetic prolyl hydroxylase inhibition}},
author = {Bar Shahar and Itay Kilimnik and Lucia Adriana Lifshits and Francesca Netti and Marina Sova and Dalia Rosin-Grunewald and Ayelet Di Segni and Maayan Gal and Lihi Adler-Abramovich},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-73451-5},
url = {https://www.nature.com/articles/s41598-026-73451-5},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Enhancing collagen biosynthesis in mammalian cells through hypoxia-mimetic prolyl hydroxylase inhibition
AU - Bar Shahar
AU - Itay Kilimnik
AU - Lucia Adriana Lifshits
AU - Francesca Netti
AU - Marina Sova
AU - Dalia Rosin-Grunewald
AU - Ayelet Di Segni
AU - Maayan Gal
AU - Lihi Adler-Abramovich
PY - 2026
DA - 2026/10/08
JO - Scientific Reports
DO - 10.1038/s41598-026-73451-5
UR - https://www.nature.com/articles/s41598-026-73451-5
AB - Collagen, the most abundant protein in the extracellular matrix of mammalian cells, is a key biomaterial in various biotechnological and therapeutic applications, such as tissue engineering and regeneration, cosmetics, and cultivated meat. Despite the increasing demand for culture-based collagen, it is still mainly produced from animal connective tissues. A recent study has shown that under hypoxia, activation of the hypoxia-inducible factor (HIF) leads to enhanced type I collagen biosynthesis. However, under normal oxygen conditions, HIF activity is downregulated by the HIF-prolyl hydroxylase (PHD) enzyme. Based on these previous findings, we hypothesized that inhibiting PHD activity by exogenous modulators could mimic hypoxia, leading to elevated HIF transcriptional activity and enhancing collagen biosynthesis under normoxia. Our study demonstrates that pharmacological PHD inhibition using a set of small molecules targeting their 2-oxoglutarate (2-OG)-dependent activity is associated with enhanced HIF activity, upregulation of key-collagen modifying enzymes, including collagen prolyl 4-hydroxylases and lysyl hydroxylases, accompanied by a 10- to 29-fold increase in collagen type I fluorescence intensity in NIH/3T3 embryonic mouse fibroblast cells. These findings show that targeting PHD can effectively enhance collagen production in mammalian cells, suggesting that the modulation of intracellular key protein signaling pathways presents a promising strategy for enhancing the production of culture-based collagen.
SN - 2045-2322
ER -