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Oxidative stress and ferroptosis are implicated in MS pathology, contributing to both inflammation and neurodegeneration. Potentially functional variants in genes related to antioxidant defense and ferroptosis were chosen through an extensive selection process to investigate their possible association with the progressive form of MS. The study included 845 MS patients (604 relapsing\u2013remitting (RRMS) and 241 progressive (PMS)). The selected gene variants\u2014GCLC rs572496, GCLM rs2273406, GPX4 rs713041, NQO1 rs1800566 and CAT rs2420388\u2014were genotyped using TaqMan\u00ae technology. mRNA expression levels of the corresponding genes in PBMCs were previously determined by targeted RNA sequencing. Circulatory molecular indicators of antioxidant defense and ferroptosis were quantified using ELISA and colorimetric enzymatic recycling assays. The findings indicate that the GCLC rs572496 variant was significantly associated with MS disease severity and had a significant effect on GCLC mRNA levels. Additionally, the NQO1 rs1800566 variant had a significant effect on NQO1 mRNA expression in PBMCs of MS patients overall. The results suggest further analysis of antioxidant defense and ferroptosis-related gene variants with MS severity and validation of the gained results in larger study groups.<\/jats:p>","DOI":"10.3390\/biology15100773","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:12:08Z","timestamp":1779455528000},"page":"773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association Between Multiple Sclerosis Severity and Functional Variants in Key Antioxidant Defense and Ferroptosis-Related Genes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9857-9828","authenticated-orcid":false,"given":"Tamara","family":"Djuric","sequence":"first","affiliation":[{"name":"Laboratory for Radiobiology and Molecular Genetics, VIN\u010cA Institute of Nuclear Sciences\u2014National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6109-9460","authenticated-orcid":false,"given":"Jovana","family":"Kuveljic","sequence":"additional","affiliation":[{"name":"Laboratory for Radiobiology and Molecular Genetics, VIN\u010cA Institute of Nuclear Sciences\u2014National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0316-8461","authenticated-orcid":false,"given":"Ana","family":"Djordjevic","sequence":"additional","affiliation":[{"name":"Laboratory for Radiobiology and Molecular Genetics, VIN\u010cA Institute of Nuclear Sciences\u2014National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4272-2370","authenticated-orcid":false,"given":"Milan","family":"Stefanovic","sequence":"additional","affiliation":[{"name":"Laboratory for Radiobiology and Molecular Genetics, VIN\u010cA Institute of Nuclear Sciences\u2014National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2945-6561","authenticated-orcid":false,"given":"Evica","family":"Dincic","sequence":"additional","affiliation":[{"name":"Clinic for Neurology, Military Medical Academy, 11000 Belgrade, Serbia"},{"name":"Medical Faculty of the Military Medical Academy, University of Defense, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8024-2832","authenticated-orcid":false,"given":"Mariana","family":"Seke","sequence":"additional","affiliation":[{"name":"Laboratory for Radiobiology and Molecular Genetics, VIN\u010cA Institute of Nuclear Sciences\u2014National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1050-5913","authenticated-orcid":false,"given":"Aleksandra","family":"Stankovic","sequence":"additional","affiliation":[{"name":"Laboratory for Radiobiology and Molecular Genetics, VIN\u010cA Institute of Nuclear Sciences\u2014National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0447-6626","authenticated-orcid":false,"given":"Maja","family":"Zivkovic","sequence":"additional","affiliation":[{"name":"Laboratory for Radiobiology and Molecular Genetics, VIN\u010cA Institute of Nuclear Sciences\u2014National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7269","DOI":"10.1007\/s10787-025-02012-5","article-title":"Multiple sclerosis pathophysiology: A comprehensive review of genetic, environmental, and immunological drivers","volume":"33","author":"Ghafoor","year":"2025","journal-title":"Inflammopharmacology"},{"key":"ref_2","unstructured":"(2026, April 27). 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