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Previous studies have shown that sustained mTOR activation may cause chronic muscle fatigue by inhibiting ATG13-mediated autophagy. However, the therapeutic implication of this finding has not been established. Given that rapamycin is an mTOR inhibitor, this study aims to investigate whether low-dose rapamycin treatment improves autophagy markers and clinical symptoms of fatigue in ME\/CFS subjects. This highlights the pivotal role of mTOR in the pathogenesis of ME\/CFS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a decentralized, uncontrolled trial of rapamycin in 86 patients with ME\/CFS to evaluate its safety and efficacy. Low-dose rapamycin (6\u00a0mg\/week) was administered, and core ME\/CFS symptoms were assessed on days 30 (T1), 60 (T2), and 90 (T3). Plasma levels of autophagy metabolites, such as pSer258-ATG13 and BECLIN-1, were measured and correlated with clinical outcomes, specifically MFI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Rapamycin (6\u00a0mg\/week) was tolerated without any SAEs. Of the 70 patients who completed at the minimum to T1, 52 (74.3%) showed recovery in fatigue, PEM, and OI, along with improvements in MFI fatigue domains and SF-36 aspects. High levels of BECLIN-1 were detected in T3. Plasma pSer258-ATG13 levels were strongly downregulated at T1. Spearman\u2019s correlation analysis indicated an association between autophagy impairment and reduced activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Low-dose rapamycin effectively reduced PEM and other key symptoms in patients with ME\/CFS, as measured by BAS, SSS, MFI, and SF-36. Future studies should encompass dose optimization and develop a diagnostic tool to identify responders with mTOR-mediated autophagy disruption.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-025-07213-8","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T10:57:07Z","timestamp":1761044227000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Low-dose rapamycin alleviates clinical symptoms of fatigue and PEM in ME\/CFS patients via improvement of autophagy: a pilot study"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1330-6806","authenticated-orcid":false,"given":"Brian T.","family":"Ruan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarojini","family":"Bulbule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke","family":"Gile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bela","family":"Chheda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucinda","family":"Bateman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Bell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brayden","family":"Yellman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie L.","family":"Grach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Berner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kaufman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0523-8504","authenticated-orcid":false,"given":"Avik","family":"Roy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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