Reframing preeclampsia via the cyclic GMP–AMP synthase–stimulator of interferon genes–glycocalyx Axis: A systematic review and trial-ready translational model
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.012 | 0.030 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.011 | 0.010 |
| Bibliometrics | 0.004 | 0.004 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".