biostudies-literatureZhang YNational Natural Science Foundation of China (National Science Foundation of China)83https://www.ebi.ac.uk/biostudies/studies/S-EPMC12923772biostudies-literatureUnknown16(1)<h4>Background</h4>Mitochondrial dysfunction has been implicated in major depressive disorder (MDD), but reliable, measurable biomarkers remain elusive. 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.<h4>Methods</h4>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 Lipták-Stouffer Z-score method. Sensitivity and fail-safe N analyses assTranslational psychiatryBlood circulating cell-free mitochondrial DNA as a potential biomarker for major depressive disorder: a meta-analysis.PMC12923772823017098237152481920108018, 82230046Zhao MChen QLi TZhang YQi XGuo WSong SWei WMeng YDeng WYu XfalseBlood circulating cell-free mitochondrial DNA as a potential biomarker for major depressive disorder: a meta-analysis.<h4>Background</h4>Mitochondrial dysfunction has been implicated in major depressive disorder (MDD), but reliable, measurable biomarkers remain elusive. 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.<h4>Methods</h4>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 Lipták-Stouffer Z-score method. Sensitivity and fail-safe N analyses ass2026-01-01T00:00:00Z2026 Feb2026-07-16T14:50:30.505Z2026-07-09T11:02:23.409ZS-EPMC129237724165181410.1038/s41398-026-03865-2