Circulating cell-free DNA in preeclampsia: predictive potential and insights into pathogenesis

Abstract Preeclampsia (PE) is a severe complication during pregnancy, and its pathogenesis is closely related to placental dysfunction. In recent years, cell-free DNA (cfDNA) has emerged as a promising non-invasive biomarker for the early prediction of PE, especially early-onset PE (EOPE). This review summarizes the latest research progress on cfDNA for PE prediction, including its biological characteristics, sources, clearance mechanisms, and level changes in PE patients. We focus on the distinct cfDNA signatures of EOPE and late-onset PE (LOPE), and explore the clinical application value of cfDNA-related features (fetal fraction, nucleosome patterns, DNA methylation, gene coverage) as early diagnostic and predictive tools, along with the performance of integrative models combining cfDNA with traditional markers. Although cfDNA demonstrates moderate to high predictive value for EOPE in early pregnancy, its clinical application still faces challenges such as standardization, specificity, and large-scale validation. Future research should clarify the mechanisms of cfDNA release, conduct multi-omics analyses and multicenter trials to promote its application in early PE diagnosis and precise management, thereby improving maternal and neonatal health.