Cited by 189Genomics, phytochemicals, and oxidative stressGlutathione Transferases and PolymorphismsRedox biology and oxidative stress

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Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Effects on KEAP1, NRF2 Activation, and Glutathione Depletion In Vitro

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Brennan, Melanie S., Matos, Maria F., Li, Bing, Hronowski, Xiaoping, Gao, Benbo, Juhasz, Peter, Rhodes, Kenneth J., Scannevin, Robert H.·2015·PLOS ONE

DOI 10.1371/journal.pone.0120254PMC PMC4368598

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Abstract

Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate), an oral therapeutic containing dimethyl fumarate (DMF) as the active ingredient, is currently approved for the treatment of relapsing multiple sclerosis. DMF is also a component in a distinct mixture product with 3 different salts of monoethyl fumarate (MEF), which is marketed for the treatment of psoriasis. Previous studies have provided insight into the pharmacologic properties of DMF, including modulation of kelch-like ECH-associated protein 1 (KEAP1), activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, and glutathione (GSH) modulation; however, those of MEF remain largely unexplored. Therefore, the aim of this study was to evaluate the in vitro effects of DMF and MEF on KEAP1 modification, activation of the NRF2 pathway, and GSH conjugation. Using mass spectrometry, DMF treatment resulted in a robust modification of specific cysteine residues on KEAP1. In comparison, the overall degree of KEAP1 modification following MEF treatment was significantly less or undetectable. Consistent with KEAP1 cysteine modification, DMF treatment resulted in nuclear translocation of NRF2 and a robust transcriptional response in treated cells, as did MEF; however, the responses to MEF were of a lower magnitude or distinct compared to DMF. DMF was also shown to produce an acute concentration-dependent depletion of GSH; however, GSH levels eventually recovered and rose above baseline by 24 hours. In contrast, MEF did not cause acute reductions in GSH, but did produce an increase by 24 hours. Overall, these studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activity as well as unique actions. These differences would be expected to result in divergent effects on downstream biology.

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Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6943 · Cited by 3,999
Multiple Sclerosis
Noseworthy, J. H., Lucchinetti, C. F., Rodriguez, M., & Weinshenker, B. G. (2000) · New England Journal of Medicine · doi:10.1056/nejm200009283431307 · Cited by 3,016
Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224
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Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., & Talalay, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172398899 · Cited by 1,947 · cited 1×
“However, in the presence of electrophiles or oxidative stress, these molecules can bind KEAP1 cysteine residues resulting in an allosteric conformational change that diminishes KEAP1-dependent degradation of NRF2 [11].”
Background
Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress
Zhang, D. D., & Hannink, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.22.8137-8151.2003 · Cited by 1,480
Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
Taguchi, K., Motohashi, H., & Yamamoto, M. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01473.x · Cited by 1,478
Regulatory Mechanisms Controlling Gene Expression Mediated by the Antioxidant Response Element
Nguyen, T., Sherratt, P. J., & Pickett, C. B. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140229 · Cited by 1,232 · cited 2×
“This allows NRF2 to accumulate and translocate to the nucleus to regulate cytoprotective genes associated with the phase II antioxidant response [12,13].”
BackgroundMethod
Untitled work
(2002) · PubMed · Cited by 1,190
Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway
Linker, R. A., Lee, D.-H., Ryan, S., van Dam, A. M., Conrad, R., Bista, P., Zeng, W., Hronowsky, X., Buko, A., Chollate, S., et al. (2011) · Brain · doi:10.1093/brain/awq386 · Cited by 1,155
Self-citation
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Balogun, E. A., Hoque, M., Gong, P., Killeen, E., Green, C. J., Foresti, R., Alam, J., & Motterlini, R. (2003) · Biochemical Journal · doi:10.1042/bj20021619 · Cited by 1,038

Flagged first, then by citations

Show all 41 references

Research works printed but not linked: 3

K Itoh, 2003, Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles, Genes Cells, 8, 379, 10.1046/j.1365-2443.2003.00640.x · DOI
TJ Schmidt, 2007, Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-L-cysteine—preparation of S-substituted thiosuccinic acid esters, Bioorg Med Chem, 15, 333, 10.1016/j.bmc.2006.09.053 · DOI
R Holland, 2010, Chemistry of the cysteine sensors in Kelch-like ECH-associated protein 1, Antioxid Redox Signaling, 13, 1749, 10.1089/ars.2010.3273 · DOI

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Wipke, B. T., Hoepner, R., Straßburger-Krogias, K., Thomas, A. M., Gianni, D., Szak, S. T., Brennan, M. S., Pistor, M., Gold, R., Chan, A., et al. (2021) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000950 · Cited by 18
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Fiedler, S. E., Kerns, A. R., Tsang, C., Tsang, V., BOURDETTE, D. N., & Salinthone, S. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.05.021 · Cited by 17
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Zingkou, E., Medoro, A., Davinelli, S., Saso, L., Sotiropoulou, G., & Pampalakis, G. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-11478-7 · Cited by 15
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“This last modification also was supported by the activity of monomethyl fumarate as an HO-I inducer [30,47].”
Method
The putative interplay between DJ-1/NRF2 and Dimethyl Fumarate: A potentially important pharmacological target
Vavougios, G. D., Zarogiannis, S. G., & Doskas, T. (2018) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2018.02.027 · Cited by 13
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Salinas, L., Figueroa, F., Montgomery, C. B., Thai, P. N., Chiamvimonvat, N., Cortopassi, G. A., & Dedkova, E. N. (2025) · Journal of the American Heart Association · doi:10.1161/jaha.124.038505 · Cited by 12
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Hyperoside alleviated N-acetyl-para-amino-phenol-induced acute hepatic injury via Nrf2 activation.
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Zhang, Y., Tang, J., Zhou, Y., Xiao, Q., Chen, Q., Wang, H., Lan, J., Wu, L., & Peng, Y. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1114897 · Cited by 12
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Background
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Oey, O., Rao, P., Luciuk, M., Mannix, C., Rogers, N. M., Sagar, P. S., Wong, A. T. Y., & Rangan, G. K. (2018) · Experimental Biology and Medicine · doi:10.1177/1535370218759313 · Cited by 12
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Zhang, Y., Zhou, Y., Tang, J., Lan, J., Kang, Y., Wu, L., & Peng, Y. (2021) · Journal of Asian Natural Products Research · doi:10.1080/10286020.2021.1949303 · Cited by 13
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Roy, N., Wyseure, T. L., Lo, I., Metzger, J., Eissler, C. L., Bernard, S. M., Bok, I., Snead, A. N., Parker, A., Green, J. C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.04.616592 · Cited by 12
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Pistono, C., Osera, C., Boiocchi, C., Mallucci, G., Cuccia, M., Bergamaschi, R., & Pascale, A. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.03.025 · Cited by 12
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Background
Characterization of the modification of Kelch-like ECH-associated protein 1 by different fumarates
Qu, L., Guo, M., Zhang, H., Chen, X., Wei, H., Jiang, L., Li, J., Chen, Z., Dai, S., & Chen, Y. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.03.059 · Cited by 11
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Lee, S., Ali, A. R., Abed, D. A., Nguyen, M.-U., Verzi, M. P., & Hu, L. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.116104 · Cited by 10
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Zivadinov, R., Hagemeier, J., Bergsland, N., Tavazzi, E., & Weinstock‐Guttman, B. (2018) · European Journal of Neurology · doi:10.1111/ene.13562 · Cited by 10
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Background
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Background
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Background
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“In a study comparing the effects of DMF and MEF, it was found that MEF elevated Nrf2 protein levels in the nucleus via a different pathway to that of DMF. Additionally, MEF demonstrated a higher level of heme oxygenase 1(HO-1) mRNA than DMF at low concentrations [41].”
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“…in Germany for decades. it was later repurposed and approved by the FDA in 2013 for the treatment of relapsing multiple sclerosis. its pharmacological mechanism of action was hypothesized to occur via covalent modification of kelch-like ecH-associated protein 1 (KeAP1) (Brennan et al. 2015).”
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Influential
Response to fumaric acid esters for plaque type psoriasis in real-world practice is largely independent of patient characteristics at baseline – a multivariable regression analysis from the German Psoriasis Registry PsoBest
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“effects of DMF in multiple sclerosis (12,13).”
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Straß, S., Geiger, J., Cloos, N., Späth, N., Geiger, S., Schwamborn, A., da Cunha, L. D. O., Martorelli, M., Guse, J., Sandri, T. L., et al. (2023) · Inflammopharmacology · doi:10.1007/s10787-023-01186-0 · Cited by 6
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“In fact, of all KEAP1 cysteines, only speciﬁc Cys residues (predominantly Cys151) were identiﬁed to be alkylated by fumarates [48], implying that not all Cys thiols are equally prone to be attacked by fumaric acid esters.”
Background
Switching from a fumaric acid ester mixture to dimethylfumarate monotherapy in psoriasis
Warren, R. B., Barker, J. N., van de Kerkhof, P., Reich, K., & Mrowietz, U. (2019) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.15644 · Cited by 4
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Background
Dimethyl fumarate is an inhibitor of pathological angiogenesis
Ng, P. Q., Huang, K., McLellan, F. C., Yang, M., Lennikov, A., Hu, Z., Chaudhary, S., Appiah, A. C., Vuong, M. L., & Shu, D. Y. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.112106 · Cited by 2
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Трофимов, А. Н., Shcherbakova, K., Schwarz, A. P., Akbay, B., Karapina, O., Myrkhiyeva, Z., Shirokov, E., Kizatov, B., Zhukanov, K., Baktursyn, A., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27156606 · Cited by 3
Modulation of Pulmonary Inflammation and the Redox Pathway In Vitro and In Vivo by Fumaric Ester
Cardoso, A. D. O. P., Figueiredo-Junior, A. T., Mineiro, P. C. D. O., Mota, E. C., Amorim, C. S., Valença, H. D. M., Gomes, A. C. C. D. A., Serra, S. S. D. S., Silva, P. L., Takiya, C. M., et al. (2025) · Antioxidants · doi:10.3390/antiox14091141 · Cited by 2
“It is well-documented that fumarates activate the Nrf2/ARE pathway, upregulating antioxidant genes such as NQO1 and HO-1 [23–25].”
Thiol modification and signaling by biological electrophiles
Schopfer, F. J., & Vitturi, D. A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90219-9.00027-3 · Cited by 1
Insights into therapeutic discovery through the Kelch domain structure of Keap1 at ambient temperature
Yilmaz, M., Sever, B., Kutlu, Y., Gül, M., Okuducu, C., Tavli, S., Otsuka, M., Fujita, M., Haliloǧlu, T., Ciftci, H. I., et al. (2025) · TURKISH JOURNAL OF BIOLOGY · doi:10.55730/1300-0152.2742 · Cited by 1
“In adults, it is indicated for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease (Brennan et al., 2015).”
Deciphering the landscape of post-translational modifications in the centrosome upon T cell activation
Lozano-Prieto, M., Jorge, I., Camafeita, E., Devesa, C. A., Barrero-Rodríguez, R., Calvo, E., Laguillo-Gómez, A., Pertusa, C., Martin-Cofreces, N. B., Vázquez, J., et al. (2025) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2025.151521 · Cited by 1
Tetrazole-containing naphthalene bis-sulfonamide Keap1-Nrf2 interaction inhibitors with unexpected binding modes
Georgakopoulos, N., Talapatra, S. K., Naidu, S. D., Dikovskaya, D., Higgins, M., Gatliff, J., Nikoloudaki, R., Schaap, M., Walker, J. M., Wardby, C., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103924 · Cited by 1
“These compounds interact with redox-sensitive cysteine residues in Keap1 to inhibit Nrf2 ubiquitination [4,5].”
EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independent KEAP1 oligomerizing molecular bridge
Bassil, C. F., Dillon, K. A., Anderson, G. R., Mayro, B., Askin, K. N., Winter, P. S., Harry, S. A., Gruber, S., Hall, T. M., Hoj, J. P., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68424-1 · Cited by 2
Diroximel fumarate confers neuroprotection via reduced Th1 responses and induction of the anti-oxidative Nrf2 pathway in experimental neuroinflammation
Freudenstein, D., Schneeweiß, A., Krenz, A., Gold, R., Linker, R. A., & Haase, S. (2026) · PLoS ONE · doi:10.1371/journal.pone.0355936 · Cited by 1
“Effects include an upregulation of several targets, including NAD(P)H dehydrogenase (quinone) 1 and heme oxygenase 1, as well as long term elevation of glutathione levels after an initial glutathione depletion by thiol group binding to DMF [5].”
Neuroprotection induced by dimethyl fumarate
Saha, L., Singh, N., & Rawat, K. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23763-8.00036-1 · Cited by 1
Clinical stage drugs utilizing cellular metabolism pathways
Ryan, T. A. J., O'Neill, L. A. J., & Zasłona, Z. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-15447-8.00012-x · Cited by 1
Convergent Signals Encode Persistent Memory of Resilient StatesPreprint
Femenía, T., Prendeville, H., Sun, N., Harmon, C., Galani, K., Grove, K. L., Lynch, L., Kellis, M., & Agudelo, L. Z. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.15.694462 · Cited by 1
SKIN REDOX BALANCE MAINTENANCE: THE NEED FOR AN NRF2- ACTIVATORS DELIVERY SYSTEM
Greenwald, M. B., Sasson, S. B., Peled, H., & Kohen, R. (2016) · doi:10.18143/jisanh_v3i3_1457
“Some examples of Nrf2 activators include sulforaphane, curcumin, epigallocatechin-3-gallate, resveratrol, garlic, oganosulfur compounds, lycopene, carnosol [223–225], nitroxides [226] and dimethyl fumarate [227].”
Background
Immune regulation by mimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis patients
Diaz, G. M. (2020) · Research Publications (Maastricht University) · doi:10.26481/dis.20201015gmd
Faculty Opinions recommendation of Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in parkinson's disease.
Lipton, S. A. (2017) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.726232983.793538943
Short-term exposure to dimethyl fumarate (DMF) inhibits LPS-induced IκBζ expression in macrophages: implications for the pharmacological activity of DMFPreprint
Zhang, Y., Tang, J., Zhou, Y., Xiao, X., Chen, Q., Wang, H., Lan, J., Wu, L., & Peng, Y. (2022) · Research Square · doi:10.21203/rs.3.rs-2308926/v1
Investigating dimethyl fumarate derivatives as drugs against oxidative stress using the molecular docking with KEAP1 protein
Emamian, S., Hosseini, J., & Ali-Asgari, S. (2025) · فصلنامه علوم پزشکی دانشگاه آزاد اسلامی واحد پزشکی تهران · doi:10.61882/iau.35.4.406
Additional file 1 of Repurposing dimethyl fumarate as an antiepileptogenic and disease-modifying treatment for drug-resistant epilepsy
Sandouka, S., Singh, P. K., Saadi, A., Taiwo, R. O., Sheeni, Y., Zhang, T., Deeb, L., Guignet, M. A., White, S. H., & Shekh‐Ahmad, T. (2023) · Figshare · doi:10.6084/m9.figshare.24531939
Profiling peripheral blood oxidative stress in multiple sclerosis
Minton, T., Hares, K. M., Kemp, K. C., Redondo, J., Scolding, N. J., & Rice, C. (2026) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2026.107039
Dimethyl fumarate combined with cisplatin at subcytotoxic doses sensitizes cervical cancer toward ferroptosis and apoptosis through GSH restriction and p53 (re)activation
Punziano, C., Minopoli, G., Romano, S., Marrone, L., Aquilano, K., Tornesello, M. L., & Faraonio, R. (2026) · Molecular Oncology · doi:10.1002/1878-0261.70216
Rôle de la CK2 dans l’activation de la réponse immunitaire induite par les molécules allergisantes et son lien avec Nrf2
de Bourayne, M. (2015) · theses.fr (ABES) · doi:10.70675/fed3e8c8z64c2z4e1ez81a9z054e2d240b5f
“De plus, il a été montré par spectrométrie de masse que le DMF modifie directement les cystéines Cys151, 257 et 273 de Keap1, entrainant la libération de Nrf2, sa translocation nucléaire et une augmentation du taux cellulaire de GSH (Brennan et al., 2015).”
Influential
Effets des activateurs pharmacologiques de Nrf2 sur la réponse antioxydante et anti-inflammatoire dans le macrophage humain
Ali, M. (2019) · theses.fr (ABES) · doi:10.70675/02b82cb4z87f6z4ff5z8744zec1377a5b248
Metabolism of new drug modalities research advances – 2025 year in review
Ma, B., Cheruzel, L., Cho, S., Hauri, S., Li, X., Liu, J., Rehm, K., Seneviratne, H. K., Seo, H., Shi, L., et al. (2026) · Drug Metabolism Reviews · doi:10.1080/03602532.2026.2663169
Dimethyl fumarate ameliorates quinolinic acid-induced ageing and neurodegeneration in Caenorhabditis elegans
Sun, Y., Zhou, K., Cui, J., Ding, H., Shareef, I., Du, L., Shi, Z., Fu, L., Sun, F., Zhu, Z., et al. (2026) · Biogerontology · doi:10.1007/s10522-026-10455-8
“The concentrations of QA, DMF and ML385 were selected based on previous literature (Ge et al. 2023; Brennan et al. 2015; Yong et al. 2024).”
Exercise-Driven NRF2 Activation as a Systemic Neuroprotective Strategy: Integrating Redox Biology, Muscle–Brain Crosstalk, and Therapeutic Targeting in Neurodegeneration
Deng, P., Deng, W., Wang, L., Ye, W., & Li, S. (2026) · Biochemical Genetics · doi:10.1007/s10528-026-11415-0
Fumaric Acid Esters as Modulators of Ocular Inflammation and Angiogenesis
Priya, S., McLellan, F. C., Wich, P. R., Kumeria, T., Willcox, M. D. P., & Shu, D. Y. (2026) · American Journal Of Pathology · doi:10.1016/j.ajpath.2026.05.014
Metabolic Modulation by Dimethyl Fumarate Alters Docetaxel Responses in Prostate Cancer Cells
Coneo–Pretelt, A., Peñata-Taborda, A., Espitia-Pérez, L., Jiménez-Vidal, L., Negrette-Guzmán, M., Jones-Cifuentes, N. A., Rincón‐Orozco, B., Aristizábal-Gutiérrez, F., & Espitia-Pérez, P. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27146209
“…axis, DMF directly modulates the glutathione (GSH) antioxidant system: it conjugates with GSH, causing acute intracellular GSH depletion, while GSH levels may subsequently recover and rise above baseline through Nrf2-mediated transcriptional upregulation of glutathione biosynthetic enzymes [16].”
Comparative Analysis of Novel Derivatives of Pyridoxine and Dicarboxylic Acids as Activators of Transcription Factor Nrf2
Балакина, А. С., Podgurskaya, A. D., Amozova, V. I., Stupina, T. S., Mumyatova, V. A., Suvorova, O. S., & Gadomsky, S. Y. (2026) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-026-06703-z
“In addition, maleate, like fumarate [12], additionally enhances the stabilization of Nrf2 and its nuclear translocation.”
Precision Covalent Drug Discovery Inspired by Endogenous Electrophilic Signalling in Immune Cells
Habtemariam, S. (2026) · Biomedicines · doi:10.3390/biomedicines14081851
“Dimethyl fumarate (Figure 1), a fumarate-derived electrophile approved for multiple sclerosis, covalently modifies reactive cysteine residues in Keap1 and activates Nrf2 signalling [48,49].”
Glutathione Biology in Neurodegenerative and Metabolic Diseases: Molecular Mechanisms, Pathophysiological Roles, and Therapeutic Perspectives
Gromadzka, G., Kąkol, M., Klimkiewicz, M., & Bendykowska, M. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27167507
“Experimental studies have consistently demonstrated that activation of the Nrf2 pathway increases intracellular GSH levels, attenuates oxidative stress, and suppresses inflammatory signaling through modulation of redox-sensitive pathways, including NF-κ B [288,289].”
Comparative multi-analyte serum protein differences between generic and brand-name dimethyl fumarate, fingolimod, and teriflunomide in multiple sclerosis
Okuda, D. T., Anderson, B. J., Taylor, S. M., Jones-McCreary, M. C., Burgess, K. W., Wright, C., Santoyo, J. R., Sguigna, P. V., Stüve, O., Tran, D. H., et al. (2026) · Clinical Immunology · doi:10.1016/j.clim.2026.110766
Particulate Matter-Induced Skin Injury: A Dual-Pathway AhR–Nrf2 Framework for Epidermal Homeostasis and Therapeutic Targeting
Lin, C.-H., Yen, C., Wu, Y., Chang, H., Ko, H., & Chen, Y. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27177573
“Representative examples include sulforaphane [201,202], dimethyl fumarate [203–205], and tert -butyl hydroquinone [204,206,207], all of which have been reported to exhibit context-dependent interactions with AhR signaling pathways.”
Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives
Chen, N., Xie, X., He, S., & Liang, L. (2026) · Immune Network · doi:10.4110/in.2026.26.e35
Proteomic Cysteine Profiling Links DMI and DMF to Antiviral Activity
Baek, J., Zhang, L., Byun, W., Kim, S. W., Kim, K., & Tomassy, G. S. (2026) · PROTEOMICS · doi:10.1002/pmic.70184
Fumarate and Its Esters: Physiology, Pathology, Molecular Mechanisms, Diseases, and Therapy
Zhu, P., You, M., Zeng, Y., Zhang, J., Chen, S., Rong, R., & Xia, X. (2026) · MedComm · doi:10.1002/mco2.71059
Dimethyl fumarate-induced mitochondrial intoxication
de Oliveira, M. R. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-45078-5.00006-3
NRF2 signalling in environmental metal and metalloid neurotoxicity: distinguishing stress responses from functional neuroprotection
Mesole, B. S., Yusuf, U. A., Okpanachi, A. O., Oria, R. S., & Bumbangi, F. N. (2026) · Frontiers in Toxicology · doi:10.3389/ftox.2026.1988769
BindingDB Entry 50023009: Covalent Inhibitors of KEAP1 with Exquisite Selectivity.
BindingDB (2026) · UC San Diego · doi:10.7270/q21z498d
BindingDB Entry 50021431: Structural modification of C2-substituents on 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acid derivatives as potent inhibitors of the Keap1-Nrf2 protein-protein interaction.
BindingDB (2025) · UC San Diego · doi:10.7270/q2542t7c
BindingDB Entry 50012368: Development and optimization of halogenated vinyl sulfones as Nrf2 activators for the treatment of Parkinson's disease.
BindingDB (2022) · UC San Diego · doi:10.7270/q2222zf3

Authors: Brennan, M. S., Matos, M. F., Li, B., Hronowski, X., Gao, B., Juhasz, P., Rhodes, K. J., & Scannevin, R. H.
Affiliations: Biogen (United States) (US)
Corresponding author: Scannevin, Robert H.
ORCID: Li, Bing
Hronowski, Xiaoping
Gao, Benbo
Scannevin, Robert H.
Venue: PLOS ONE
Publisher: Public Library of Science (PLoS)
Published: 2015-03-20
Volume: 10
Issue: 3
Pages: e0120254
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0120254
PMC: PMC4368598
OpenAlex: W2008817720
Cited by: 188
References: 41
Citations by year: 2026: 23 · 2025: 19 · 2024: 15 · 2023: 14 · 2022: 21 · 2021: 11 · 2020: 13 · 2019: 16 · 2018: 18 · 2017: 14 · 2016: 17 · 2015: 6
FWCI: 7.96
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Funders: Biogen
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: dimethyl fumarate, Keap1, Nrf2 activation, glutathione depletion, cysteine modification, nuclear translocation, antioxidant pathways, multiple sclerosis, psoriasis, fumarate salts
MeSH terms: Dimethyl Fumarate, Kelch-Like ECH-Associated Protein 1, Astrocytes, Cell Nucleus, Cysteine, Extracellular Space, Fumarates, Gene Expression Regulation, Glutathione, Humans, Protein Transport, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2, HEK293 Cells

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Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Effects on KEAP1, NRF2 Activation, and Glutathione Depletion In Vitro

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