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As a minimally invasive and quantifiable biomarker, circulating cell-free mitochondrial DNA (ccf-mtDNA) in blood offers potential for objective assessment of mitochondrial stress in MDD. However, evidence linking regarding the association between ccf-mtDNA levels and MDD is limited and inconsistent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically searched eight databases, including PubMed, EMBASE, and major Chinese repositories. Thirteen studies with 1370 participants (837 individuals with MDD and 533 controls) were included per PRISMA guidelines. P-values were synthesized using the Lipt\u00e1k-Stouffer Z-score method. Sensitivity and fail-safe N analyses assessed the robustness of the findings and publication bias, and stratified analyses examined the effects of age, antidepressant use, and geographic region.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Across studies, elevated blood ccf-mtDNA levels were significantly associated with MDD (p\u2009=\u20090.013). Stratified analyses revealed stronger associations in older adults (\u226560 years old; p\u2009=\u20090.0009), unmedicated patients (p\u2009=\u20094.99\u2009\u00d7\u200910\u207b\u2076), and North American cohorts (p\u2009=\u20094.29\u2009\u00d7\u200910\u207b\u00b9\u00b9), but not in younger individuals (p\u2009=\u20090.83), medicated patients (p\u2009=\u20090.97), and Asian\/European samples (p\u2009=\u20090.72, p\u2009=\u20090.99). Sensitivity analyses indicated moderate instability overall but confirmed data robustness in key subgroups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This is the first meta-analysis to establish a significant link between elevated blood ccf-mtDNA and MDD, highlighting age and antidepressant exposure as critical modulators. These findings support the potential of blood ccf-mtDNA to serve as a biomarker for late-life and drug-na\u00efve depression, with implications for objective diagnosis and personalized treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41398-026-03865-2","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T17:16:03Z","timestamp":1770398163000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Blood circulating cell-free mitochondrial DNA as a potential biomarker for major depressive disorder: a meta-analysis"],"prefix":"10.1038","volume":"16","author":[{"given":"Yaman","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhe","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueli","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4109-3878","authenticated-orcid":false,"given":"Wei","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanjun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3831-901X","authenticated-orcid":false,"given":"Xueyu","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"3865_CR1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/s41392-024-01738-y","volume":"9","author":"L Cui","year":"2024","unstructured":"Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, et al. 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