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PreprintCited by 10Cystic Fibrosis Research AdvancesGenomics, phytochemicals, and oxidative stressCurcumin's Biomedical Applications

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Curcumin-mediated NRF2 induction limits inflammatory damage in preclinical models of cystic fibrosis

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Leon-Icaza, Stephen A, Fretaud, Maxence, Cornélie, Sarahdja, Bureau, Charlotte, Yatime, Laure, Floto, R Andres, Renshaw, Stephen A, Herrmann, Jean-Louis, Langevin, Christelle, Cougoule, Céline, Bernut, Audrey·2024·Biomedicine & Pharmacotherapy
DOI 10.1101/2024.03.17.585384

Preprint — published as 10.1016/j.biopha.2025.117957 · Paper page

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Abstract

Overactive inflammation is directly correlated with airway damage and early death in individuals with cystic fibrosis (CF), a genetic disorder caused by mutation in the CFTR gene. Reducing the impact of inflammatory damage is therefore a major concern in CF. Several studies indicate that a decrease in the nuclear factor erythroid 2-related factor-2 (NRF2) signaling in people with CF may hamper their ability to alleviate oxidative stress and inflammation, although the role of NRF2 in CF inflammatory damage has not been determined. Therefore, we examined whether the phytochemical curcumin, an activator of NRF2, might provide a beneficial effect in the context of CF. Herein, combining Cftr -depleted zebrafish larvae as innovative biomedical model with CF patient-derived airway organoids (AOs), we sought to understand how NRF2 dysfunction leads to abnormal inflammatory status and impaired tissue remodeling, and determine the effects of curcumin in reducing inflammation and tissue damage in CF. We demonstrate that NFR2 is instrumental in efficiently regulating inflammatory and repair processes in vivo , thereby preventing acute neutrophilic inflammation and tissue damage. Importantly, curcumin treatment restores NRF2 activity in both CF zebrafish and AOs. Curcumin reduces neutrophilic inflammation in CF context, by rebalancing the production of epithelial ROS and pro-inflammatory cytokines. Furthermore, curcumin alleviates CF-associated tissue remodeling and allows tissue repair to occur. Our findings demonstrate that curcumin reduces inflammatory damage by restoring normal NRF2 activity, since disruption of Nrf2 pathway abrogated the effect of treatment in CF zebrafish. This work highlights the protective role of NRF2 in limiting inflammation and injury, and show that therapeutic strategies to normalize NRF2 activity using curcumin might simultaneously reduce inflammation and enhance tissue repair, and thus prevent infectious and inflammatory lung damage in CF.

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Metadata

Authors
Leon-Icaza, S. A., Fretaud, M., Cornélie, S., Bureau, C., Yatime, L., Floto, R. A., Renshaw, S. A., Herrmann, J.-L., Langevin, C., Cougoule, C., & Bernut, A.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • University of Sheffield (GB)
  • Inserm (FR)
  • Université Paris-Saclay (FR)
Corresponding author
Bernut, Audrey
ORCID
Venue
Biomedicine & Pharmacotherapy
Publisher
openRxiv
Published
2024-03-17
Volume
186
Pages
117957-117957
ISSN
0753-3322 (ISSN-L)
DOI
10.1101/2024.03.17.585384
OpenAlex
W4409093563
Cited by
10
References
1
Citations by year
2026: 6 · 2025: 4
FWCI
6.61
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Biomedicine & Pharmacotherapy (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
  • HAL (submittedVersion, cc-by)
Funders
  • Cystic Fibrosis Trust (SRC018, 160161)
  • Fondation pour la Recherche Médicale (ARF201909009156)
  • Association Vaincre la Mucoviscidose (RF20210502852/1/1/48)
  • Université de Montpellier
  • Université de Versailles Saint-Quentin-en-Yvelines
  • Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (IERP-UE907)
  • Horizon 2020 Framework Programme (MSCA-IF-2016, H2020-MSCA, 955576, H2020-MSCA-IF-2016, H2020-MSCA-ITN-2020, H2020-MSCA-ITN)
  • H2020 Marie Skłodowska-Curie Actions (751977, 955576)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Curcumin's Biomedical Applications
Keywords
cystic fibrosis, curcumin, Nrf2 signaling, neutrophilic inflammation, airway inflammation, airway organoids, zebrafish model, CFTR, reactive oxygen species, inflammatory cytokines, airway fibrosis, tissue repair, Nrf2 activators
MeSH terms
Animals, Curcumin, Cystic Fibrosis, Disease Models, Animal, Humans, Inflammation, Neutrophils, Zebrafish, Reactive Oxygen Species, Cystic Fibrosis Transmembrane Conductance Regulator, Zebrafish Proteins, Animals, Genetically Modified, NF-E2-Related Factor 2

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