Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts.
Overview
- Institute of Human Genetics, University Hospital of Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Center for Rare Diseases, University Hospital of Cologne, University of Cologne, Cologne, Germany
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.
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Data
Datasets cited
- zenodo:19068620, at Zenodo; found in “Data Availability Statement”
Data Availability Statement
All data supporting the findings of this study have been deposited in Zenodo and are publicly available at: https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 2, 28 September 2026
- Publisher: n/a → 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://
BibTeX
@article{vrettou2026phar
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/
url = {https://
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/
VL - 40
IS - 12
SP - e72064
SN - 0892-6638
PB - Wiley
DO - 10.1096/
UR - https://
LA - en
ER -
CSL-JSON
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