Cell-free DNA in female infertility: from pathological mechanisms to clinical biomarkers

Female infertility, accounting for 40–50% of infertility cases globally, underscores the urgent need for non-invasive biomarkers to guide early intervention. Cell-free DNA (cfDNA)—released via apoptosis, necrosis, or active secretion—has emerged as a dynamic molecular reflector of tissue pathophysiology. This review synthesizes recent advances in cfDNA biology and their clinical applications in female infertility. Mechanistically, cfDNA drives inflammation, oxidative stress, and neutrophil extracellular traps (NETs), exacerbating dysfunction in polycystic ovary syndrome (PCOS), endometriosis (EMs), and premature ovarian insufficiency (POI). Clinically, cfDNA characteristics in follicular fluid or plasma serve as diagnostic-prognostic tools: reduced mitochondrial cfDNA (cf-mtDNA) in PCOS signifies oocyte mitochondrial damage; elevated long-fragment ratios in EMs/POI reflect chronic inflammation; and low cfDNA integrity in assisted reproductive technology (ART) predicts poor embryo quality. Despite challenges in standardization and ethics, future integration with multi-omics platforms is poised to translate cfDNA analysis into precision reproductive medicine.