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While the exact causes remain unclear, recent research highlights the significant role of epigenetic modifications and mitochondrial dysfunction in the disease\u2019s onset and progression. Epigenetic alterations, such as DNA methylation, histone modification, and microRNA regulation, influence gene expression without altering the DNA sequence, leading to immune dysregulation and inflammation. Similarly, mitochondrial dysfunction, marked by impaired oxidative phosphorylation, reduced adenosine triphosphate (ATP) production, and increased reactive oxygen species (ROS), contributes to neurodegeneration and impaired remyelination in MS. The growing interest in targeting these two interconnected mechanisms has opened new avenues for MS treatment. Herbal drugs, known for their multi-targeted effects, have shown potential in modulating epigenetic markers and enhancing mitochondrial function. Compounds such as resveratrol, curcumin, epigallocatechin-3-gallate (EGCG), quercetin, and omega-3 fatty acids demonstrate potential in regulating DNA methylation, histone deacetylation, and mitochondrial biogenesis. These natural agents offer dual-action therapies by reducing oxidative stress and inflammation while promoting neuronal survival and remyelination. This review explores the therapeutic potential of herbal drugs targeting epigenetic and mitochondrial pathways in MS, evaluating their mechanisms of action and highlighting their promise as novel therapeutic agents. While initial findings are encouraging, further research and clinical trials are required to validate the efficacy of these herbal treatments and fully understand their potential in slowing disease progression and improving patient outcomes in MS. Such exploration could pave the way for safer, multi-targeted therapies, offering new hope in the management of MS and other neurodegenerative diseases.\n<\/jats:p>","DOI":"10.1007\/s12035-025-04868-8","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T06:42:42Z","timestamp":1743835362000},"page":"10045-10090","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Epigenetic and Mitochondrial Metabolic Dysfunction in Multiple Sclerosis: A Review of Herbal Drug Approaches and Current Clinical Trials"],"prefix":"10.1007","volume":"62","author":[{"family":"Ashwani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayank Kumar","family":"Choudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalapathi","family":"Gugulothu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Pandita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surajpal","family":"Verma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8106-9066","authenticated-orcid":false,"given":"Lalitkumar K.","family":"Vora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharmendra Kumar","family":"Khatri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debapriya","family":"Garabadu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"issue":"17 Suppl","key":"4868_CR1","first-page":"s321","volume":"19","author":"K Noyes","year":"2013","unstructured":"Noyes K, Weinstock-Guttman B (2013) Impact of diagnosis and early treatment on the course of multiple sclerosis. 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