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Epstein-Barr virus (EBV) infection and vitamin D deficiency have been put forward as causal factors for the development of MS, but their effects have not been conclusively linked to the disruption of myelin maintenance. Interestingly, both EBV infection and vitamin D deficiency increase the levels of hepcidin, an acute-phase peptide hormone that inhibits iron absorption. The current understanding of iron dysregulation in MS is that iron accumulates in deep gray matter brain structures which leads to disability progression. However, recent studies have revealed that the apparent iron influx may be an artefact of disease-related brain atrophy, and that iron is in contrast\n                    <jats:italic>depleted<\/jats:italic>\n                    in the deep gray matter in MS, which could cause iron deficiency in oligodendrocytes (the cells producing myelin), leading to their demise due to a mitochondrial energy deficit, with consequent demyelination. EBV infection, vitamin D deficiency and iron deficiency may converge as causal risk factors for MS. Dismantling the current understanding that iron excess underpins MS would improve testing and optimization of iron parameters and vitamin D as part of clinical management of MS. This review additionally explores the risk factors for lytic reactivation of EBV which is hypothesized to drive MS disease activity. Conversely, ensuring that EBV remains in a latent state by ameliorating these risk factors may prevent MS exacerbations and disease worsening.\n                  <\/jats:p>","DOI":"10.1007\/s11011-025-01678-8","type":"journal-article","created":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T09:33:52Z","timestamp":1759570432000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Epstein-Barr virus infection and vitamin D deficiency are both \u201ccausal\u201d for multiple sclerosis (MS) - could the common denominator be their effects on hepcidin levels?"],"prefix":"10.1007","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2437-8978","authenticated-orcid":false,"given":"Susan J.","family":"van Rensburg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2689-065X","authenticated-orcid":false,"given":"Ronald","family":"van Toorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2929-0972","authenticated-orcid":false,"given":"Mariaan","family":"Jaftha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5126-6982","authenticated-orcid":false,"given":"Merlisa C.","family":"Kemp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1084-769X","authenticated-orcid":false,"given":"Penelope","family":"Engel-Hills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6050-2876","authenticated-orcid":false,"given":"Maritha J.","family":"Kotze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,4]]},"reference":[{"key":"1678_CR1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1080\/1028415X.2019.1659560","volume":"24","author":"WA Al Ammar","year":"2021","unstructured":"Al Ammar WA, Albeesh FH, Ibrahim LM, Algindan YY, Yamani LZ, Khattab RY (2021) Effect of omega-3 fatty acids and fish oil supplementation on multiple sclerosis: a systematic review. 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Kotze is a nonexecutive director and shareholder of Gknowmix [Pty] Ltd, a spin-out company of the South African Medical Research Council and Susan J. van Rensburg is the scientific advisor at Gknowmix [Pty] Ltd. Susan J. van Rensburg previously served on the Editorial Board of Metabolic Brain Disease. The remaining authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"No writing assistance or AI program was used to write this article. The manuscript was assessed by Turnitin to identify unintentional similarity to previously published work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Use of AI"}}],"article-number":"279"}}