{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:34:34Z","timestamp":1760060074912,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["U01NS106845-01A1"],"award-info":[{"award-number":["U01NS106845-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ricerca Corrente 2025\u20132027, Italian Ministry of Health","award":["U01NS106845-01A1"],"award-info":[{"award-number":["U01NS106845-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Aicardi-Gouti\u00e8res Syndrome (AGS) is a rare neuroinflammatory condition characterized by early-onset symptoms that extend outside the nervous system. Due to the rarity of the disease, the pathogenesis is not well understood, and its diagnosis and treatment remain elusive. We recently demonstrated mitochondrial abnormalities and increased reactive oxygen species (ROS) levels in lymphoblastoid cell lines (LCLs) derived from RNASEH2B- and RNASEH2A-mutated AGS patients. On this background, we turned our attention to metformin, the first-choice drug for type 2 diabetes, as a possible treatment acting on oxidative stress in RNASEH2-mutant AGS cells. Methods and Results: By means of flow cytometry, we found that metformin treatment significantly decreases ROS production in RNASEH2B- and RNASEH2A-mutated AGS LCLs. Of note, metformin treatment reduces the green JC-1 monomeric signal and, concurrently, increases the red JC-1 signal in both mutated LCLs, accounting for restoration of the mitochondrial membrane potential. Immunofluorescence staining shows a decrease in 8-oxoG levels only in RNASEH2B- mutated AGS LCLs. Finally, the significant upregulation of Forkhead Box O3 (FOXO3), cytochrome C somatic (CYCS), and superoxide dismutase 2 (SOD2) mRNA levels in RNASEH2B-mutated AGS LCLs after metformin treatment points to FOXO3 signaling as a possible mechanism to reduce oxidative stress. Conclusions: In conclusion, even if these pilot results need to be confirmed on a larger cohort, we shed light on metformin treatment as a valid approach to ameliorate oxidative stress-related inflammation in AGS patients.<\/jats:p>","DOI":"10.3390\/genes16080922","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:29:02Z","timestamp":1753885742000},"page":"922","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin Reduces Oxidative Damage in RNASEH2-Mutant Aicardi-Gouti\u00e8res Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7608-3306","authenticated-orcid":false,"given":"Francesca","family":"Dragoni","sequence":"first","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9885-1369","authenticated-orcid":false,"given":"Jessica","family":"Garau","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5799-7732","authenticated-orcid":false,"given":"Bartolo","family":"Rizzo","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8947-9342","authenticated-orcid":false,"given":"Simona","family":"Orcesi","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"},{"name":"Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5645-021X","authenticated-orcid":false,"given":"Costanza","family":"Varesio","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"},{"name":"Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7834-0342","authenticated-orcid":false,"given":"Rosalinda","family":"Di Gerlando","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"},{"name":"Department of Biology and Biotechnology \u201cL. Spallanzani\u201d, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9461-756X","authenticated-orcid":false,"given":"Matteo","family":"Bordoni","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6703-1755","authenticated-orcid":false,"given":"Eveljn","family":"Scarian","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9571-0862","authenticated-orcid":false,"given":"Cristina","family":"Cereda","sequence":"additional","affiliation":[{"name":"Department of Pediatric, Buzzi Children\u2019s Hospital, 20154 Milan, Italy"},{"name":"Department of Biomedical and Clinical Sciences, University of Milan, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3041-0612","authenticated-orcid":false,"given":"Orietta","family":"Pansarasa","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6589-6907","authenticated-orcid":false,"given":"Stella","family":"Gagliardi","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1086\/521373","article-title":"Clinical and molecular phenotype of Aicardi-Goutieres syndrome","volume":"81","author":"Rice","year":"2007","journal-title":"Am. 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