Megan Ellis

Background: Multiple sclerosis (MS) is an autoimmune disease involving inflammatory demyelination and axonal transection in the CNS neurons due to an inappropriate response to myelin antigens.^1,4 MS results in physical and cognitive disability as well as a severe decrease in quality of life.^1,4 About 1 million people in the US were diagnosed with MS as of 2019.⁸  Current treatment options utilize symptom management and immune system suppression. This is not curative, not effective in all patients, and places the patient at risk due to immune compromise.^1,3,4 Ferroptosis is a method of regulated cell death that involves iron mediated lipid peroxidation and is recognized to play a role in the multiple sclerosis disease process.⁵ There are currently no treatments that mitigate the role of cell death, including ferroptosis, in MS.⁴ Ferrostatin-1 (Fer-1) is a synthetic antioxidant that has been shown to inhibit ferroptosis and may be a candidate for use in multiple sclerosis.

Objective: To elicit the mechanism by which ferrostatin-1 inhibits ferroptosis in the setting of multiple sclerosis.

Search Methods: PubMed database was searched for keywords including: ferrostatin-1; ferroptosis; multiple sclerosis; multiple sclerosis AND ferroptosis; ferrostatin-1 AND multiple sclerosis; ferrostatin-1 AND mechanism; including results from 2017-2026.

Results: Fer-1 reduced ferroptosis and clinical severity in a mouse MS model.⁶ Experimental autoimmune encephalomyelitis is a commonly used mouse model of MS induced by immunization. When fer-1 was administered concurrently with immunization, phenotypic clinical severity was significantly decreased and histopathological assay showed significantly reduced levels of ferroptosis products when compared to controls.⁶ Mechanistically, fer-1 reduces ferroptosis by inhibiting lipid peroxidation.⁵ It does so in two ways. First, it interrupts at the initiation stage by neutralizing the initiating alkoxyl radicals as shown by its ability to efficiently inhibit lipid peroxidation when iron-dependent generation of alkoxyl radicals is used as the initiating molecule compared to lipid hydroperoxyl radicals.⁵ This is further supported by the analysis of liposomal model products that align with total reduction in products consistent with inhibition at the initiation stage.⁵ Secondly, it reduces the iron-dependent initiation of lipid peroxidation by binding and neutralizing iron in a pseudocatalytic manner.⁵ Fer-1 levels were shown by spectrophotometry to remain almost identical to the control condition while inhibiting peroxidation.⁵ Additionally, the ratio of ferrous to ferric iron as well as fer-1 was equal and consistent with fer-1-iron complex and iron reduction cycle.⁵ Additionally, by labeling labile iron with calcein, it was shown that fer-1 reduces the labile iron pool.⁵ This, combined with quantum physical computational modeling supporting the ability of fer-1 to bind and oxidize labile iron, supports fer-1 acting similar to a catalyst while forming a fer-1-iron complex to neutralize initiating iron molecules.⁵

Conclusion: Fer-1 has been shown to be able to reduce lipid peroxidation and ferroptosis from a mechanistic and mouse model level. This indicates Fer-1 may be a strong candidate for use in treating disorders that heavily depend on ferroptosis for pathogenesis, such as MS. Prior to human clinical trials, more mouse model studies should be performed to further confirm the impact of Fer-1 on multiple sclerosis.

Works Cited:

1. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and Treatment of Multiple Sclerosis: A Review. JAMA. 2021;325(8):765-779. doi:10.1001/jama.2020.26858
2. Van San E, Debruyne AC, Veeckmans G, et al. Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression. Cell Death Differ. 2023;30(9):2092-2103. doi:10.1038/s41418-023-01195-0
3. Dobson R, Giovannoni G. Multiple sclerosis – a review. European Journal of Neurology. 2019;26(1):27-40. doi:10.1111/ene.13819
4. Olejnik P, Roszkowska Z, Adamus S, Kasarełło K. Multiple sclerosis: a narrative overview of current pharmacotherapies and emerging treatment prospects. Pharmacol Rep. 2024;76(5):926-943. doi:10.1007/s43440-024-00642-0
5. Miotto G, Rossetto M, Di Paolo ML, et al. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol. 2020;28:101328. doi:10.1016/j.redox.2019.101328
6. Li X, Chu Y, Ma R, et al. Ferroptosis as a mechanism of oligodendrocyte loss and demyelination in experimental autoimmune encephalomyelitis. Journal of Neuroimmunology. 2022;373:577995. doi:10.1016/j.jneuroim.2022.577995
7. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222
8. Nelson LM, Wallin MT, Marrie RA, et al. A new way to estimate neurologic disease prevalence in the United States. Neurology. 2019;92(10):469-480. doi:10.1212/WNL.0000000000007044