Peripheral blood 24S-hydroxycholesterol as a trans-etiological early warning biomarker and its mechanism in IUGR-associated neurodevelopmental disorders

Abstract Background Early identification of neurodevelopmental disorders associated with intrauterine growth restriction (IUGR) following diverse prenatal stressors remains challenging due to etiological heterogeneity and the lack of specific non-invasive biomarkers. Methods We utilized a multi-tiered approach integrating astrocyte-specific ATP-binding cassette sub-family G member 1 ( Abcg1 ) knockout mice, two classical IUGR animal models exposed to distinct prenatal environmental stressors (caffeine and dexamethasone), and a sex-stratified clinical cohort of IUGR infants. Hippocampal synaptic ultrastructure, neurobehavioral performance, and 24S-hydroxycholesterol (24S-HC) levels in both brain tissue and peripheral blood were assessed to investigate the role of disrupted cholesterol homeostasis in IUGR-associated neurodevelopmental disorders. Results ABCG1 deficiency or IUGR consistently induced hippocampal synaptic ultrastructural damage and neurobehavioral abnormalities, accompanied by concurrent reductions of 24S-HC levels in both brain tissue and peripheral blood. In the clinical cohort, circulating 24S-HC levels were significantly diminished in both male and female IUGR infants. Receiver operating characteristic (ROC) analyses demonstrated the strong predictive performance of 24S-HC for adverse neurodevelopmental outcomes, while sex-stratified logistic regression analyses confirmed that lower 24S-HC levels were independently associated with an increased risk of neurodevelopmental abnormalities. Conclusions These findings establish dysregulated cholesterol metabolism as a shared mechanistic pathway underlying neurodevelopmental injury across diverse IUGR etiologies. Furthermore, they identify peripheral blood 24S-HC as an early, non-invasive, and predictive biomarker, offering a novel strategy for precise clinical intervention in high-risk infants.