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Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts.

Overview

Authors: Sofia Vrettou1,2, Sebastian Zetzsche2, Brunhilde Wirth1,2,3
ORCID iDs: Sofia Vrettou, Brunhilde Wirth
  1. Institute of Human Genetics, University Hospital of Cologne, University of Cologne, Cologne, Germany
  2. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
  3. Center for Rare Diseases, University Hospital of Cologne, University of Cologne, Cologne, Germany
Institutions: University of Cologne (Germany); University Hospital Cologne (Germany)
Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, volume 40, issue 12, article e72064
Dates: received 19 March 2026; accepted 10 June 2026; published online 16 June 2026; in print 30 June 2026
Type: Brief report · Language: English
License: CC BY
Identifiers: DOI 10.1096/fj.202601358r · PMID 42301137 · PMCID PMC13271045 · OpenAlex W7164889686
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: human (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: human fibroblasts, NRF2‐KEAP1 signaling, omaveloxolone, oxidative stress, redox homeostasis, spinal muscular atrophy
MeSH: Fibroblasts*, Muscular Atrophy, Spinal*, NF-E2-Related Factor 2*, Triterpenes*, Cell Survival, Cells, Cultured, Humans, Kelch-Like ECH-Associated Protein 1, NAD(P)H Dehydrogenase (Quinone), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Signal Transduction, Up-Regulation (* major topic)
Topic: Neurogenetic and Muscular Disorders Research (Genetics, Medicine), according to OpenAlex
Funding: EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA) (956185); UzK | Center for Molecular Medicine Cologne, University of Cologne (CMMC, UoC) (C18)
Citations: not cited yet (Europe PMC); 31 references in the paper

Abstract

Spinal muscular atrophy (SMA) is caused by loss of SMN protein and is increasingly recognized as a multisystem disorder involving molecular pathology beyond motor neurons. Recently, we identified dysregulated NRF2‐KEAP1 signaling in SMA mice. Since NRF2 coordinates transcriptional programs that maintain cellular redox homeostasis and adaptive stress responses, we investigated whether NRF2 signaling is similarly altered in fibroblasts derived from individuals with SMA type I and whether it can be pharmacologically engaged. Compared with control fibroblasts, SMA fibroblasts displayed reduced basal expression of NRF2 target proteins, including NQO1 and xCT (SLC7A11), along with decreased levels of PGC1α. Omaveloxolone (OMAV), a pharmacological NRF2 activator approved for the treatment of Friedreich's ataxia, increased cell viability and upregulated NRF2 target proteins in both control and SMA fibroblasts. Notably, OMAV produced a modest increase in SMN protein abundance and PGC1α levels selectively in SMA cells. Together, these findings support diminished NRF2 pathway activity as a feature of SMA fibroblasts and demonstrate that OMAV activates NRF2 signaling in this human SMA cellular model, consistent with enhanced cytoprotective signaling. These results support further investigation of NRF2 activation, including OMAV, as a potential adjunctive strategy in SMA.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data Availability Statement

All data supporting the findings of this study have been deposited in Zenodo and are publicly available at: https://doi.org/10.5281/zenodo.19068620.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 2, 28 September 2026

  • Publisher: — → Wiley

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 6 keywords, 12 MeSH terms, 2 funders, 30 references.

Cite

This paper

Vrettou, S., Zetzsche, S., & Wirth, B. (2026). Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 40(12), e72064. https://doi.org/10.1096/fj.202601358r

BibTeX

@article{vrettou2026pharmacological,
author = {Vrettou, Sofia and Zetzsche, Sebastian and Wirth, Brunhilde},
title = {{Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts}},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
year = {2026},
month = jun,
volume = {40},
number = {12},
pages = {e72064},
publisher = {Wiley},
issn = {0892-6638},
doi = {10.1096/fj.202601358r},
url = {https://doi.org/10.1096/fj.202601358r},
pmid = {42301137},
pmcid = {PMC13271045}
}

RIS

TY - JOUR
AU - Vrettou, Sofia
AU - Zetzsche, Sebastian
AU - Wirth, Brunhilde
TI - Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts
T2 - FASEB journal : official publication of the Federation of American Societies for Experimental Biology
J2 - FASEB J
PY - 2026
DA - 2026/06/01
VL - 40
IS - 12
SP - e72064
SN - 0892-6638
PB - Wiley
DO - 10.1096/fj.202601358r
UR - https://doi.org/10.1096/fj.202601358r
LA - en
ER -

CSL-JSON

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