Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Effects on KEAP1, NRF2 Activation, and Glutathione Depletion In Vitro
Open accessAbstract
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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In Mtb-infected Irg1-deficient mice, pro-inflammatory cytokine production including IL-6 and IL-1β is increased.
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From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [73]
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“this effect was independent of its ability to act as an anti-bactericidal agent73.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [73]
The effect of Irg1 on neutrophil recruitment is thought to be a consequence of itaconate-mediated transcriptional regulation of the inflammatory response.
“an effect thought to be a consequence of itaconate-mediated transcriptional regulation of the inflammatory response73.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [73]
Irg1 impairs neutrophil recruitment to the lungs to curtail excessive lung inflammation and pathology.
“Irg1 was shown to specifically impair neutrophil recruitment to the lungs to curtail excessive lung inflammation and pathology”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [73]
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“[55] TABLE 2 Chemical structure and basic properties of FA, DMF, MMF and MEF (adapted from Brennan et al. 2015)[40] Compound Molecular formula Molecular weight Melting points (°C) Molecular structure Fumaric acid C4H4O4 116.07 287 DMF C6H8O4 144.13 102 MMF C5H6O4 130.1 144 MEF C6H8O4 144.13 147 F…”
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“Contrary to the previously reported covalent modification at the cysteine residue 151 of the Keap1 protein after DMF treatment (38, 39), HPPE treatment failed to modify Keap1 cysteines (SI Appendix, Fig.”
Modulation of Keap1/Nrf2/ARE Signaling Pathway by Curcuma- and Garlic-Derived Hybrids
Serafini, M. M., Catanzaro, M., Fagiani, F., Simoni, E., Caporaso, R., Dacrema, M., Romanoni, I., Govoni, S. M., Racchi, M., Daglia, M., et al. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01597 · Cited by 81 · see citing works
“The concentrations for DMF were chosen basing on literature data (Brennan et al., 2015; Campolo et al., 2018) and a range of concentrations starting from 1 mM to 50 mM has been analyzed.”
BackgroundMethodBrennan, M. S., Matos, M. F., Richter, K. E., Li, B., & Scannevin, R. H. (2017) · Scientific Reports · doi:10.1038/srep42054 · Cited by 87 · see citing works
Self-citationThe Role of Organosulfur Compounds as Nrf2 Activators and Their Antioxidant Effects
Egbujor, M. C., Petrosino, M., Zuhra, K., & Saso, L. (2022) · Antioxidants · doi:10.3390/antiox11071255 · Cited by 76 · see citing works
“Accordingly, in mouse embryonic fibroblasts (MEFs) harboring triple cysteine sensor mutation on Keap1, in which the three cysteines Cys151, Cys273 and Cys288 were substituted with serine, tryptophan, and glutamic acid, respectively, activation of the Nrf2 pathway in response to Class IV activators (but not Class I–III…”
BackgroundInfluentialChakkittukandiyil, A., Sajini, D. V., Karuppaiah, A., & Selvaraj, D. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105325 · Cited by 73 · see citing works
Dimethyl fumarate modulates antioxidant and lipid metabolism in oligodendrocytes
Huang, H., Taraboletti, A., & Shriver, L. P. (2015) · Redox Biology · doi:10.1016/j.redox.2015.04.011 · Cited by 70 · see citing works
“Cells were seeded in 6-well plates at a density of 3.0 105 cells/mL for the 24 h experiments or 1.0 105 cells/mL for experiments lasting 72 h.”
MethodInfluentialDimethyl fumarate potentiates oncolytic virotherapy through NF-κB inhibition
Selman, M., Ou, P., Rousso, C., Bergeron, A., Krishnan, R., Pikor, L., Chen, A., Keller, B., Ilkow, C., Bell, J., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao1613 · Cited by 57 · see citing works
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The Complex Genetic and Epigenetic Regulation of the Nrf2 Pathways: A Review
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“Curcumin [45] and sulforaphane [46,47]—both widely used “antioxidant” supplements—and dimethyl fumarate [48]—the pharmaceutical therapy marketed as Tecfidera® for the treatment of multiple sclerosis—all show this ability to deplete glutathione.”
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“4), despite the well-established role for NRF2 in fumarate mediated cellular responses (Scannevin et al., 2012; Brennan et al., 2015).”
BackgroundResultSelf-citationDimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions
Zinger, N., Ponath, G., Sweeney, E., Nguyen, T. D., Lo, C. H., Diaz, I., Dimov, A., Teng, L., Zexter, L., Comunale, J., et al. (2022) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000001138 · Cited by 51 · see citing works
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Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation
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“The induction of Nrf2 is achieved through glutathione depletion as well as direct binding of fumaric acid esters to the Nrf2 repressor KEAP1.(3,6,7) The antioxidant effects of DMF were initially considered to be the primary mechanism of action for this disease-modifying treatment (DMT), as mice lacking Nrf2 did not re…”
BackgroundSkin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System
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“In astrocytes, acute exposure of the derivative dimethyl fumarate depletes intracellular GSH, but increases total GSH at later timepoints [25].”
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Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis
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“DMF also exerts its clinical effects through activation of Nrf2 (Brennan et al., 2015).”
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Dimethyl Fumarate: A Review in Relapsing-Remitting MS
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“SFN and DMF mediate stabilization and nuclear translocation of Nrf2 by modulating the inhibitory protein of Nrf2, kelch-like ECH-associated protein 1 (Keap1) [62,63].”
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“DMI is also a far more potent Nrf2 activator, as the lack of a negative charge leads to a push toward the Michael equation (14, 110) (Table 2).”
BackgroundLee, J., Song, K., Hiebert, P., Werner, S., Kim, T., & Kim, Y. S. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2019.12.008 · Cited by 41 · see citing works
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“DMF is known to react with glutathione (GSH) rapidly and to provoke a quick depletion of its reduced form [26,27], which could affect the mitochondrial respiratory chain efficiency.”
BackgroundAdvances in developing noncovalent small molecules targeting Keap1
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Proteomics and Beyond: Cell Decision-Making Shaped by Reactive Electrophiles
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“Furthermore, Keap1, a protein labeled by Tecfidera[62, 63], was not detectable by ABPP.”
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Homocysteine Induces Glial Reactivity in Adult Rat Astrocyte Cultures
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Inhibiting the Keap1/Nrf2 Protein‐Protein Interaction with Protein‐Like Polymers
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NRF2 in neurodegenerative diseases
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“Recent studies have proposed that fumaric acid esters such as dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) can activate genes associated with the Nrf2 antioxidant response pathway [20,31].”
BackgroundLiu, L., Vollmer, M. K., Kelly, M. G., Fernandez, V. M., Fernandez, T. G., Kim, H., & Doré, S. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01760-0 · Cited by 35 · see citing works
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“Among tested positive controls, DMF is known to activate Nrf2 protein through canonical mechanisms such as the modification of Keap 1 Cys residues [52].”
BackgroundThe role of NRF2 transcription factor in inflammatory skin diseases
Salman, S., Paulet, V., Hardonnière, K., & Kerdine‐Römer, S. (2025) · BioFactors · doi:10.1002/biof.70013 · Cited by 37 · see citing works
“157,169 Other bioactive nat-ural compounds have also shown promise in alleviating psoriasis.”
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Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases
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“We then performed explorative experiments to evaluate the potential Nrf2 pathway activation in HREC exposed to the same range of DMF concentrations for 6 h; this time was selected according to our experience of the D F’s rapid action evidenced in other cellular models [31,32].”
MethodProtective effects of monomethyl fumarate at the inflamed blood–brain barrier
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Regulation of proteostasis and innate immunity via mitochondria-nuclear communication
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An updated patent review of Nrf2 activators (2020-present)
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“The most notable treatment options/strategies for Nrf2 agonism are carnosol (Martin et al., 2004), monascin (Lee et al., 2013), dimethyl fumarate (Brennan et al., 2015), chemerin (Zhang, Xu et al., 2018), and ankaflavin (Lee et al., 2012; Wang et al., 2018; Zhao, Sun, Zhang et al., 2015).”
BackgroundMetabolic ROS Signaling: To Immunity and Beyond
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NRF2 , a crucial modulator of skin cells protection against vitiligo, psoriasis, and cancer
Panieri, E., Telkoparan‐Akillilar, P., & Saso, L. (2022) · BioFactors · doi:10.1002/biof.1912 · Cited by 27 · see citing works
“Since its approval, the formulation of dimethyl fumarate and monoethyl fumarate (DMF/MEF) has represented a mainstay in the treatment of psoriasis,118,119 with proven clinical efficacy against moderate to severe forms.120–122 While initial studies provided evidence that DMF could attenuate the severity of neuroinflamm…”
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“An emerging body of experimental evidence suggests that DMF, targeting Keap1 and interfering with the Nrf2/Keap1 interaction, indirectly activates Nrf2 by enabling its translocation into the nucleus [3].”
BackgroundMin, J., COHAN, S. L., Álvarez, E., Sloane, J. A., Phillips, J. T., van der Walt, A., Koulinska, I. N., Fang, F., Miller, C., & Chan, A. (2019) · Neurology and Therapy · doi:10.1007/s40120-019-0127-2 · Cited by 26 · see citing works
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“…when clinicians exploit these agents therapeutically— S-alkylation thus acts as a pharmacological “kill switch”, but at the expense of widespread glutathione depletion (notably via DMF-mediated succination of Keap1 Cys151) and the risk of off-target alkylations across the proteome [155,174].”
Duarte, P., Michalska, P., Crisman, E., Cuadrado, A., & Leon, R. M. (2022) · Antioxidants · doi:10.3390/antiox11020247 · Cited by 24 · see citing works
“A prominent example of this process is the DMF mechanism of action whose derived metabolite, monomethyl fumarate (MMF), reacts with KEAP1-Cys151 to induce the NRF2-ARE pathway activation [37].”
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“In vitro studies have shown that, even if to a lower degree, MMF also directly enhances Nrf2′s pathway but causes less intranuclear accumulation of the NFR2 protein compared to DMF [12].”
BackgroundInfluence of TNF ‐alpha inhibitors and fumaric acid esters on male fertility in psoriasis patients
Heppt, F., Colsman, A., Maronna, A., Uslu, U., Heppt, M. V., Kiesewetter, F., & Sticherling, M. (2017) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.14364 · Cited by 23 · see citing works
Dimethyl Fumarate and Intestine: From Main Suspect to Potential Ally against Gut Disorders
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“Another strategy might be the direct use of MMF, which is characterized by better GI tolerability and exerts protective effects against gastric ulcerations [145,146], although several studies in the literature in different contexts underline the higher efficacy of DMF compared to MMF [147,148].”
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“Furthermore, the Nrf2 activators CDDO-Me, SFN, and DMF have been shown to modify glutathione levels (Tarozzi et al., 2009; Reisman et al., 2012; Brennan et al., 2015).”
BackgroundDimethylfumarate ameliorates hepatic injury and fibrosis induced by carbon tetrachloride
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Emerging small-molecule treatments for multiple sclerosis: focus on B cells
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Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
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“…activity that was the effect of natural products or their active principles on nociception based on animal models (acetic acid-induced abdominal writhing, formalin-induced nociception, orofacial formalin-induced nociception tests, chronic muscle pain tests, tail flick tests, hot plate tests, tail…”
BackgroundMethodSynthesis, In Vitro and In Silico Studies of HO-1 Inducers and Lung Antifibrotic Agents
Pittalà, V., Vanella, L., Platania, C. B. M., Salerno, L., Raffaele, M., Amata, E., Marrazzo, A., Floresta, G., Romeo, G., Greish, K. F., et al. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2018-0448 · Cited by 17 · see citing works
- 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.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-03-20
- Volume
- 10
- Issue
- 3
- Pages
- e0120254
- ISSN
- 1932-6203 (ISSN-L)
- 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 · 2014: 1
- FWCI
- 7.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- 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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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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