Complement C3 as a marker for blood-brain barrier leakage after burn injury

Burns can lead to blood-brain barrier (BBB) disruption, triggering severe neurological complications. However, not all patients with mild thermal injury develop BBB leakage, and reliable peripheral biomarkers to identify concomitant BBB disruption remain lacking.

This study aimed to identify a peripheral blood biomarker for detecting post-burn BBB disruption and to elucidate the molecular mechanisms driving this endothelial dysfunction.

Mass spectrometry and Enzyme-Linked Immunosorbent Assay (ELISA) techniques were employed to screen potential circulating biomarkers. Diagnostic value was assessed via receiver operating characteristic (ROC) curve analysis using independent training and validation cohorts. Cellular mechanisms were investigated using in vivo and in vitro models, combined with transcriptomics, transmission electron microscopy, and behavioral assessments.

Proteomic analysis identified complement C3 as a highly specific rule-in biomarker for detecting post-burn BBB disruption. C3 demonstrated robust diagnostic accuracy, yielding an area under the curve (AUC) of 0.978 in the training cohort and 0.855 in the validation cohort (with 100% specificity), particularly for cortical BBB leakage within the optimal 0-6 h post-injury window. Mechanistically, activation of the C3a/C3aR axis promoted mitochondrial dysfunction and maladaptive mitophagy in endothelial cells, leading to compromised BBB integrity, enhanced neuroinflammation, and cognitive impairment.

Peripheral blood C3 serves as a highly specific biomarker for the early risk stratification of burn-induced cortical BBB disruption. Furthermore, the C3a/C3aR-mediated maladaptive mitophagy pathway drives this endothelial injury, offering novel targets for timely clinical intervention.