Abstract / Summary
Introduction: Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) is a platelet- and endotheliumassociated glycoprotein implicated in platelet activation, thrombus propagation, and endothelial injury. Because these processes underpin thrombo-inflammatory cardiovascular and cardiopulmonary diseases, circulating SCUBE1 has attracted interest as a candidate biomarker. This systematic review aimed to critically synthesize comparative clinical evidence on circulating SCUBE1 levels across thrombotic or ischemic cardiovascular and cardiopulmonary conditions relative to control or comparator groups.
Materials and methods: A systematic search of PubMed, ScienceDirect, and SpringerLink was conducted for Englishlanguage studies published from 1 January 2015 to 27 September 2025. The protocol was prospectively registered in PROSPERO (CRD420251178563). Eligibility was guided by a PECO framework and included observational and diagnostic accuracy studies that measured circulating SCUBE1 in serum or plasma and reported patientcomparator data. Two reviewers independently screened studies, extracted data, and assessed methodological quality using design-specific Joanna Briggs Institute tools and ROBINS-I. Owing to clinical and methodological heterogeneity, findings were synthesized narratively without meta-analysis.
Results: Nine studies were included (four cross-sectional, three case-control, one cohort, and one diagnostic accuracy study). SCUBE1 levels were generally higher in patients with thrombotic or ischemic cardiovascular and cardiopulmonary diseases than in comparators, supporting associations with platelet-endothelial activation, thrombotic burden, endothelial dysfunction, and ischemia-reperfusion stress. However, absolute concentrations varied markedly across studies, precluding direct comparison and limiting interpretability of proposed cut-off values. Eight studies had moderate risk of bias and one had serious risk.
Conclusion: SCUBE1 is a biologically plausible but still investigational biomarker; robust multicenter prospective studies with standardized assays are required before clinical translation in routine clinical practice.