Fumarate-based drugs protect against neuroinflammation via upregulation of anti-ferroptotic pathways

Lassmann H. Pathology of inflammatory diseases of the nervous system: human disease versus animal models. Glia. 2020;68(4):830–44.

Article  PubMed  Google Scholar 

Absinta M, Lassmann H, Trapp BD. Mechanisms underlying progression in multiple sclerosis. Curr Opin Neurol. 2020;33(3):277–85.

Article  PubMed  PubMed Central  Google Scholar 

Bierhansl L, Hartung HP, Aktas O, Ruck T, Roden M, Meuth SG. Thinking outside the box: non-canonical targets in multiple sclerosis. Nat Rev Drug Discov. 2022;21(8):578–600.

Article  PubMed  PubMed Central  Google Scholar 

Kirschner P, Pawlitzki M, Hartung HP, Meuth SG. Immunology of multiple sclerosis: an update. Curr Opin Neurol. 2025;38(3):180–7.

Article  PubMed  Google Scholar 

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.

Article  PubMed  PubMed Central  Google Scholar 

Berndt C, Alborzinia H, Amen VS, Ayton S, Barayeu U, Bartelt A, et al. Ferroptosis in health and disease. Redox Biol. 2024;75:103211.

Article  PubMed  PubMed Central  Google Scholar 

Kemp K, Redondo J, Hares K, Rice C, Scolding N, Wilkins A. Oxidative injury in multiple sclerosis cerebellar grey matter. Brain Res. 2016;1642:452–60.

Article  PubMed  Google Scholar 

Hu CL, Nydes M, Shanley KL, Morales Pantoja IE, Howard TA, Bizzozero OA. Reduced expression of the ferroptosis inhibitor glutathione peroxidase-4 in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurochem. 2019;148(3):426–39.

Article  PubMed  Google Scholar 

Li X, Chu Y, Ma R, Dou M, Li S, Song Y, et al. Ferroptosis as a mechanism of oligodendrocyte loss and demyelination in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2022;373:577995.

Article  PubMed  Google Scholar 

Hametner S, Dal Bianco A, Trattnig S, Lassmann H. Iron related changes in MS lesions and their validity to characterize MS lesion types and dynamics with ultra-high field magnetic resonance imaging. Brain Pathol. 2018;28(5):743–9.

Article  PubMed  PubMed Central  Google Scholar 

Dunham J, Bauer J, Campbell GR, Mahad DJ, van Driel N, van der Pol SMA, et al. Oxidative injury and iron redistribution are pathological hallmarks of marmoset experimental autoimmune encephalomyelitis. J Neuropathol Exp Neurol. 2017;76(6):467–78.

Article  PubMed  Google Scholar 

Lassmann H, van Horssen J. Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta. 2016;1862(3):506–10.

Article  PubMed  Google Scholar 

Stojkovic L, Djordjevic A, Stefanovic M, Stankovic A, Dincic E, Djuric T, et al. Circulatory indicators of lipid peroxidation, the driver of ferroptosis, reflect differences between relapsing-remitting and progressive multiple sclerosis. Int J Mol Sci. 2024;25:11024. https://doi.org/10.3390/ijms252011024.

Article  PubMed  PubMed Central  Google Scholar 

Van San E, Debruyne AC, Veeckmans G, Tyurina YY, Tyurin VA, Zheng H, et al. Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression. Cell Death Differ. 2023;30(9):2092–103.

Article  PubMed  PubMed Central  Google Scholar 

Dietrich M, Hecker C, Nasiri M, Samsam S, Issberner A, Kohne Z, et al. Neuroprotective properties of dimethyl fumarate measured by optical coherence tomography in Non-inflammatory animal models. Front Neurol. 2020;11:601628.

Article  PubMed  Google Scholar 

Kocur M, Schneider R, Pulm AK, Bauer J, Kropp S, Gliem M, et al. IFNbeta secreted by microglia mediates clearance of Myelin debris in CNS autoimmunity. Acta Neuropathol Commun. 2015;3:20.

Article  PubMed  PubMed Central  Google Scholar 

Lepka K, Volbracht K, Bill E, Schneider R, Rios N, Hildebrandt T, et al. Iron-sulfur glutaredoxin 2 protects oligodendrocytes against damage induced by nitric oxide release from activated microglia. Glia. 2017;65(9):1521–34.

Article  PubMed  Google Scholar 

Popova NV. [Transplancental effect of ortho-aminoazotoluene on organ cultures of embryonal liver from mouse lines C57BL and CBA]. Biull Eksp Biol Med. 1977;83(6):732–4.

Article  PubMed  Google Scholar 

Lowin T, Apitz M, Anders S, Straub RH. Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner. Arthritis Res Ther. 2015;17:321.

Article  PubMed  PubMed Central  Google Scholar 

Albrecht P, Bouchachia I, Goebels N, Henke N, Hofstetter HH, Issberner A, et al. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation. 2012;9:163.

Article  PubMed  PubMed Central  Google Scholar 

Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134(Pt 3):678–92.

Article  PubMed  Google Scholar 

Yousuf MS, Moreno MM, Woodall BJ, Thakur V, Li J, He L, et al. Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decrease ISR activation in DRG neurons. Diabetes. 2025;74:827–37.

Zhu H, Yang Y, Duan Y, Zheng X, Lin Z, Zhou J. Nrf2/FSP1/CoQ10 axis-mediated ferroptosis is involved in sodium aescinate-induced nephrotoxicity. Arch Biochem Biophys. 2024;759:110100.

Article  PubMed  Google Scholar 

Ufer C, Borchert A, Kuhn H. Functional characterization of cis- and trans-regulatory elements involved in expression of phospholipid hydroperoxide glutathione peroxidase. Nucleic Acids Res. 2003;31(15):4293–303.

Article  PubMed  PubMed Central  Google Scholar 

Jhelum P, Zandee S, Ryan F, Zarruk JG, Michalke B, Venkataramani V, et al. Ferroptosis induces detrimental effects in chronic EAE and its implications for progressive MS. Acta Neuropathol Commun. 2023;11(1):121.

Article  PubMed  PubMed Central  Google Scholar 

Jhelum P, Santos-Nogueira E, Teo W, Haumont A, Lenoel I, Stys PK, et al. Ferroptosis mediates cuprizone-induced loss of oligodendrocytes and demyelination. J Neurosci. 2020;40(48):9327–41.

Article  PubMed  PubMed Central  Google Scholar 

Saverio V, Ferrario E, Monzani R, Gagliardi M, Favero F, Cora D, et al. AKRs confer oligodendrocytes resistance to differentiation-stimulated ferroptosis. Redox Biol. 2025;79:103463.

Article  PubMed  Google Scholar 

Cheng H, Wang P, Wang N, Dong W, Chen Z, Wu M, et al. Neuroprotection of NRF2 against ferroptosis after traumatic brain injury in mice. Antioxidants. 2023. https://doi.org/10.3390/antiox12030731.

Article  PubMed  PubMed Central  Google Scholar 

Qi D, Chen P, Bao H, Zhang L, Sun K, Song S, et al. Dimethyl fumarate protects against hepatic ischemia-reperfusion injury by alleviating ferroptosis via the NRF2/SLC7A11/HO-1 axis. Cell Cycle. 2023;22(7):818–28.

Article  PubMed  Google Scholar 

Yan N, Xu Z, Qu C, Zhang J. Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-kappaB signal pathway. Int Immunopharmacol. 2021;98:107844.

Article  PubMed  Google Scholar 

Yang Y, Cai F, Zhou N, Liu S, Wang P, Zhang S, et al. Dimethyl fumarate prevents ferroptosis to attenuate acute kidney injury by acting on NRF2. Clin Transl Med. 2021;11(4):e382.

Article  PubMed  PubMed Central  Google Scholar 

Zhu X, Lu H, Jia H, Wei X, Xue J, Li W, et al. Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes. J Transl Med. 2025;23(1):280.

Article  PubMed  PubMed Central  Google Scholar 

Liu Y, Luo X, Chen Y, Dang J, Zeng D, Guo X, et al. Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis. Redox Biol. 2024;69:103008.

Article  PubMed 

Comments (0)

No login
gif