Abstract
Intracerebral hemorrhage (ICH) remains a major cause of morbidity and mortality, with no rapid blood-based biomarkers available to assess secondary brain injury. This study aimed to identify a circulating pan-cell death protein signature for diagnosing and prognosing ICH. We prospectively enrolled 60 ICH patients and 60 age/sex-matched healthy controls, collecting plasma at defined time points after ICH onset. Using Olink proteomics, we identified 13 apoptosis-related proteins with significant dysregulation. Four key proteins─TLR4, ALOX15, FTL, and BMF─were validated through ELISA and RT-qPCR, showing good diagnostic performance (AUCs 0.799-0.835). A multiprotein logistic model demonstrated excellent diagnostic accuracy (AUC = 0.955). These biomarkers correlated with clinical severity and prognosis, including hematoma volume and a 90-day modified Rankin Scale (mRS). Additionally, animal models confirmed time-dependent upregulation of TLR4 in astrocytes. This pan-cell death protein signature provides valuable insights into ICH pathology and offers a promising tool for early diagnosis, risk stratification, and therapeutic targeting.