Reframing preeclampsia via the cyclic GMP–AMP synthase–stimulator of interferon genes–glycocalyx Axis: A systematic review and trial-ready translational model

Abstract Preeclampsia (PE) remains a leading cause of maternal–fetal morbidity, yet its molecular basis and validated biomarkers remain uncertain. This review proposes a mechanistic synthesis linking innate immune sensing through the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway with endothelial glycocalyx (eGCX) integrity, reframing PE as an immune–vascular interface disorder. A systematic search of PubMed, Scopus, Web of Science, and Cochrane Library through June 2025 was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020. Studies exploring molecular or structural interactions among placental cell-free DNA or mitochondrial DNA (cfDNA/mtDNA), cGAS–STING activation, and eGCX degradation in PE or mechanistically relevant endothelial models were included. Thirty-five publications met eligibility criteria, spanning human cohorts, preclinical experiments, and reviews. Quality appraisal using Newcastle–Ottawa Scale, SYstematic Review Center for Laboratory animal Experimentation, and A MeaSurement Tool to Assess Systematic Reviews-2 tools indicated predominantly low-to-moderate bias. Across studies, converging evidence suggests that placental cfDNA and mtDNA may activate cGAS–STING– interferon signaling, promoting endothelial inflammation, heparanase upregulation, and syndecan-1 shedding. The resulting eGCX disruption coincides with reduced sphingosine-1-phosphate levels and angiogenic imbalance, features consistent with early endothelial stress. Most mechanistic insights derive from animal and nonpregnancy models; therefore, their direct applicability to human gestation should be interpreted cautiously given the unique immunological environment of pregnancy. Potential translational pathways include sulodexide, pravastatin, and Soluble fms-like Tyrosine Kinase-1 apheresis as clinically supported strategies, whereas STING inhibitors remain experimental proof-of-concept tools. In summary, this synthesis proposes the cGAS–STING–eGCX axis as a conceptual framework rather than an established paradigm, emphasizing testable hypotheses for early prediction and endothelial protection in PE. The model aligns with the World Health Organization 2030 maternal health target, advocating a shift from reactive to anticipatory care through biomarker-guided surveillance.