Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis

Friedreich ataxia (FA) is a rare, multisystemic neurodegenerative disorder caused by a deficiency of the mitochondrial protein frataxin. It is characterized by degeneration of the large sensory neurons in the dorsal root ganglia (DRG) and spinocerebellar tracts, leading to progressive neurodegenerat...

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Autores: Portillo-Carrasquer, Marta, Sanz Alcázar, Arabela, Sánchez López, Begoña, Delaspre, Fabien, Pazos-Gil, Maria, Oliveira-Jorge, Luiza, Castells i Roca, Laia, Tamarit Sumalla, Jordi, Ros Salvador, Joaquim, Cabiscol Català, Elisa
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2026
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/469670
Acceso en línea:https://doi.org/10.1016/j.biopha.2026.119031
https://hdl.handle.net/10459.1/469670
Access Level:acceso abierto
Palabra clave:Friedreich ataxia
Dorsal root ganglia
Ferroptosis
Fibroblasts
Honokiol
Omaveloxolone
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network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis
title Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis
spellingShingle Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis
Portillo-Carrasquer, Marta
Friedreich ataxia
Dorsal root ganglia
Ferroptosis
Fibroblasts
Honokiol
Omaveloxolone
title_short Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis
title_full Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis
title_fullStr Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis
title_full_unstemmed Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis
title_sort Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis
dc.creator.none.fl_str_mv Portillo-Carrasquer, Marta
Sanz Alcázar, Arabela
Sánchez López, Begoña
Delaspre, Fabien
Pazos-Gil, Maria
Oliveira-Jorge, Luiza
Castells i Roca, Laia
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
Cabiscol Català, Elisa
author Portillo-Carrasquer, Marta
author_facet Portillo-Carrasquer, Marta
Sanz Alcázar, Arabela
Sánchez López, Begoña
Delaspre, Fabien
Pazos-Gil, Maria
Oliveira-Jorge, Luiza
Castells i Roca, Laia
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
Cabiscol Català, Elisa
author_role author
author2 Sanz Alcázar, Arabela
Sánchez López, Begoña
Delaspre, Fabien
Pazos-Gil, Maria
Oliveira-Jorge, Luiza
Castells i Roca, Laia
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
Cabiscol Català, Elisa
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Friedreich ataxia
Dorsal root ganglia
Ferroptosis
Fibroblasts
Honokiol
Omaveloxolone
topic Friedreich ataxia
Dorsal root ganglia
Ferroptosis
Fibroblasts
Honokiol
Omaveloxolone
description Friedreich ataxia (FA) is a rare, multisystemic neurodegenerative disorder caused by a deficiency of the mitochondrial protein frataxin. It is characterized by degeneration of the large sensory neurons in the dorsal root ganglia (DRG) and spinocerebellar tracts, leading to progressive neurodegeneration and muscle weakness. Frataxin deficiency induces iron dyshomeostasis, defective energy production, and oxidative stress, all regulated by NRF2. Omaveloxolone, an NRF2 activator, is currently the only approved therapy for FA; however, its effects on DRG neurons remain unknown. Here we used frataxin-deficient DRG neurons to better understand the drug's role in these sensory neurons. Omaveloxolone improved most of the analyzed parameters, including frataxin levels, cell survival, mitochondrial respiratory activity, iron homeostasis, oxidative stress, transferrin receptor 1 and glutathione peroxidase 4 levels, as well as the GSH/GSSG ratio. Moreover, lipid peroxidation, a key marker of ferroptosis that was increased in frataxin-deficient neurons, was almost completely rescued by omaveloxolone. Both total and nuclear NRF2 levels were decreased in frataxin-deficient neurons, and omaveloxolone treatment fully prevented this alteration. In addition, most of these results were validated in fibroblasts from FA patients. We also evaluated a combinatorial treatment using low doses of omaveloxolone together with honokiol, a SIRT3 activator with known neuroprotective properties. This combination enhanced cell survival and produced a synergistic effect increasing mitochondrial respiration in frataxin-deficient DRG neurons. In summary, these findings demonstrate the beneficial effects of omaveloxolone and further suggest that combination therapy with honokiol may provide an effective strategy for the treatment of FA, potentially mitigating adverse effects.
publishDate 2026
dc.date.none.fl_str_mv 2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1016/j.biopha.2026.119031
https://hdl.handle.net/10459.1/469670
https://hdl.handle.net/10459.1/469670
url https://doi.org/10.1016/j.biopha.2026.119031
https://hdl.handle.net/10459.1/469670
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118296RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PDC2021-120758-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2023-148128OB-I00
Reproducció del document publicat a https://doi.org/10.1016/j.biopha.2026.119031
Biomedicine and Pharmacotherapy, 2026, vol. 195, 119031
dc.rights.none.fl_str_mv cc-by-nc-nd, (c) Marta Portillo Carrasquer et al., 2026
Attribution-NonCommercial-NoDerivatives 4.0 International
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
rights_invalid_str_mv cc-by-nc-nd, (c) Marta Portillo Carrasquer et al., 2026
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosisPortillo-Carrasquer, MartaSanz Alcázar, ArabelaSánchez López, BegoñaDelaspre, FabienPazos-Gil, MariaOliveira-Jorge, LuizaCastells i Roca, LaiaTamarit Sumalla, JordiRos Salvador, JoaquimCabiscol Català, ElisaFriedreich ataxiaDorsal root gangliaFerroptosisFibroblastsHonokiolOmaveloxoloneFriedreich ataxia (FA) is a rare, multisystemic neurodegenerative disorder caused by a deficiency of the mitochondrial protein frataxin. It is characterized by degeneration of the large sensory neurons in the dorsal root ganglia (DRG) and spinocerebellar tracts, leading to progressive neurodegeneration and muscle weakness. Frataxin deficiency induces iron dyshomeostasis, defective energy production, and oxidative stress, all regulated by NRF2. Omaveloxolone, an NRF2 activator, is currently the only approved therapy for FA; however, its effects on DRG neurons remain unknown. Here we used frataxin-deficient DRG neurons to better understand the drug's role in these sensory neurons. Omaveloxolone improved most of the analyzed parameters, including frataxin levels, cell survival, mitochondrial respiratory activity, iron homeostasis, oxidative stress, transferrin receptor 1 and glutathione peroxidase 4 levels, as well as the GSH/GSSG ratio. Moreover, lipid peroxidation, a key marker of ferroptosis that was increased in frataxin-deficient neurons, was almost completely rescued by omaveloxolone. Both total and nuclear NRF2 levels were decreased in frataxin-deficient neurons, and omaveloxolone treatment fully prevented this alteration. In addition, most of these results were validated in fibroblasts from FA patients. We also evaluated a combinatorial treatment using low doses of omaveloxolone together with honokiol, a SIRT3 activator with known neuroprotective properties. This combination enhanced cell survival and produced a synergistic effect increasing mitochondrial respiration in frataxin-deficient DRG neurons. In summary, these findings demonstrate the beneficial effects of omaveloxolone and further suggest that combination therapy with honokiol may provide an effective strategy for the treatment of FA, potentially mitigating adverse effects.This work was supported by: 1) Grant PID2020–118296RB-I00 funded by MICIU/AEI /10.13039/501100011033; 2) Grant PDC2021–120758-I00 funded by MICIU/AEI /10.13039/501100011033 and by the European Union NextGenerationEU/ PRTR; 3) Grant PID2023–148128OB-I00 funded by MICIU/AEI /10.13039/501100011033 and by FEDER, EU; 4) Project 2021-SGR 00323 funded by Generalitat de Catalunya. Marta Portillo-Carrasquer received a PhD fellowship from the Generalitat de Catalunya. Arabela Sanz-Alcázar received first a Ph.D. fellowship from the Generalitat de Catalunya and after, she held predoctoral fellowship “Ajuts al Personal Investigador en Formació " from IRBLleida/Diputació de Lleida. Begoña Sánchez López received a Ph.D. fellowship “Ayudas para la formación de Personal Investigador (FPI-2023)” from Ministerio de Ciencia, Innovación y Universidades. Maria Pazos received a PhD fellowship from the Universitat de Lleida. Luiza Olivera Jorge received a predoctoral fellowship “Ajuts de suport a departaments i unitats de recerca universitaris per a la contractació de personal investigador predoctoral en formació.Elsevier2026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1016/j.biopha.2026.119031https://hdl.handle.net/10459.1/469670https://hdl.handle.net/10459.1/469670reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118296RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PDC2021-120758-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2023-148128OB-I00Reproducció del document publicat a https://doi.org/10.1016/j.biopha.2026.119031Biomedicine and Pharmacotherapy, 2026, vol. 195, 119031cc-by-nc-nd, (c) Marta Portillo Carrasquer et al., 2026Attribution-NonCommercial-NoDerivatives 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/oai:recercat.cat:10459.1/4696702026-05-29T05:05:01Z
score 15,812429

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