suPAR as a circulating inflammatory biomarker: time for translation into clinical practice - A systematic review

Urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored cell surface receptor composed of three homologous domains (DI, DII, and DIII), forming a flexible structure that mediates interactions with multiple ligands. Through these interactions, uPAR plays a key role in extracellular matrix (ECM) remodeling, cell invasion, proliferation, and migration, making it a promising therapeutic target in various diseases. In addition to its membrane-bound form, uPAR can be released into circulation following cleavage of its GPI anchor, generating soluble uPAR (suPAR), which is detectable in blood, serum, plasma, urine, and other biological fluids. Proteolytic cleavage within the linker region between domains I and II produces three main isoforms: full-length suPAR (suPAR_I-III), suPAR domain I (suPAR_DI), and suPAR domains II-III (suPAR_DII-III). suPAR has been extensively investigated as a biomarker of systemic chronic inflammation across multiple conditions. During COVID-19 pandemic, suPAR gained attention as a predictor of disease severity and mortality in acute patients, reinforcing its role as a marker of sepsis. Elevated suPAR levels have also been reported in diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and various malignancies, supporting its diagnostic and prognostic value. Several analytical methods are currently available for suPAR quantification, including ELISA, turbidimetric immunoassays, and chemiluminescence immunoassays. However, these assays differ in their ability to detect specific isoforms, which may vary in biological and clinical significance. This review summarizes the clinical relevance of suPAR, examines the functional roles of its isoforms, and evaluates current detection methods and their implications for clinical practice.