The β-hCG-TNF-α-T cell axis in threatened abortion: unraveling the pathogenic cascade from aberrant glycosylation to inflammatory demise

Threatened abortion (TA), vaginal bleeding before 20 weeks in a viable pregnancy, affects 20-25% of early pregnancies. Its unpredictable nature is a major clinical challenge. Current diagnostics (β-hCG and ultrasound) are retrospective and fail to reveal the dynamic pathology. This review presents the “Danger Signal” Hypothesis, focusing on the β-hCG-TNF-α-T cell axis, to explain TA pathogenesis. The process involves three stages: 1) Initiation: Stressed trophoblasts secrete aberrantly glycosylated β-hCG, which acts as a DAMP. 2) Amplification: This DAMP triggers a TNF-α-dominated cytokine storm, reprogramming T cell metabolism to glycolysis and sustaining inflammation. 3) Execution: The inflammatory microenvironment induces trophoblast pyroptosis, creating a vicious cycle of damage. We synthesize evidence from glycobiology, immunometabolism, and cell death research to substantiate this model, explore its implications for the development of stage-specific biomarkers (such as β-hCG glycoforms and GSDMD-N fragments), and discuss precision therapeutic approaches (including the use of metformin for metabolic intervention and anti-TNF-α agents for managing late-phase inflammation). This mechanistic framework aims to guide future research and improve clinical outcomes.