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Mito-TEMPO (MIT) is a mitochondrial-specific antioxidant that has demonstrated benefits in many cancerous, renal, cardiovascular, and neurodegenerative disorders. However, the therapeutic effect of MIT on FM remains ambiguous. The objective of the current work is to illuminate the use of MIT for FM and its prospective mechanisms. Here, we used the FM rat model induced by three days of subcutaneous reserpine injection (1\u00a0mg\/kg) and examined the role of MIT on SIRT1 activation and other implicated molecular pathways. Behavioral tests showed that MIT (0.7\u00a0mg\/kg) can effectively alleviate the locomotor, nociceptive, and depressive-like behaviors in reserpinized rats, an effect that simultaneously reconciles the balance of monoamines in the rat brain. Western blot analysis showed that MIT up-regulates SIRT1 and improves the expression of mitochondrial dynamics proteins (DRP1 and OPA1) and the endoplasmic reticulum protein (CHOP). Furthermore, MIT treatment significantly enhanced the SOD and CAT activities and decreased the brain contents of NF-\u03baB, TNF-\u03b1, and BAX, but significantly enriching the Bcl-2 content. Lastly, MIT treatment significantly reduced the genetic expression of miRNA-320 following RES treatment. All the measured parameters showed a significant correlation with SIRT1 expression. Our results suggest that MIT provides antioxidant, anti-apoptotic, and anti-inflammatory impacts on the FM rat model, with proposed mechanisms involved activating the SIRT1 pathway to regulate mitochondrial dynamics, endoplasmic reticulum stress, as well as miRNA-320. Thus, MIT has the potential to be an effectual drug candidate for FM treatment.<\/jats:p>","DOI":"10.1007\/s11064-025-04424-9","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T08:40:08Z","timestamp":1748421608000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mito-TEMPO Mitigates Fibromyalgia Induced by Reserpine in Rats: Orchestration Between SIRT1, Mitochondrial Dynamics, Endoplasmic Reticulum and miRNA-320"],"prefix":"10.1007","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6502-516X","authenticated-orcid":false,"given":"Heba S.","family":"Zaky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7264-7415","authenticated-orcid":false,"given":"Nermin T.","family":"El-Said","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3513-9235","authenticated-orcid":false,"given":"Amany S.","family":"Aboutaleb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0914-7845","authenticated-orcid":false,"given":"Albatoul","family":"Allam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1760-8277","authenticated-orcid":false,"given":"Mona","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8634-6210","authenticated-orcid":false,"given":"Hebatalla I.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7715-6156","authenticated-orcid":false,"given":"Somaia A.","family":"Abdel-Sattar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"4424_CR1","doi-asserted-by":"publisher","first-page":"174480691881994","DOI":"10.1177\/1744806918819944","volume":"15","author":"S D\u2019Agnelli","year":"2019","unstructured":"D\u2019Agnelli S, Arendt-Nielsen L, Gerra MC, Zatorri K, Boggiani L, Baciarello M, Bignami E (2019) Fibromyalgia: genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers. 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