Beyond fibrinolysis: the multifaceted role of the fibrinolytic system in systemic sclerosis

Purpose of review: This review summarizes the emerging role of the fibrinolytic system in the pathogenesis of systemic sclerosis (SSc) and its potential as a source of novel therapeutic targets. Recent findings: Increasing evidence indicates that SSc is characterized by impaired fibrinolysis, largely driven by upregulation of plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin, which limits extracellular matrix degradation and promotes myofibroblast differentiation. A key pathogenic mechanism involves matrix metalloproteinase-12-mediated proteolytic cleavage of the urokinase-type plasminogen activator receptor (uPAR), which compromises angiogenesis and promotes endothelial-to-mesenchymal transition, thereby contributing to both vascular remodeling and fibrosis. Moreover, aberrant crosstalk between cleaved uPAR and N-formyl peptide receptors (FPRs) on fibroblasts induces excessive reactive oxygen species generation and sustained fibroblast proliferation. Clinically, circulating soluble uPAR and PLAUR gene polymorphisms have emerged as candidate biomarkers of severe microvascular dysfunction and internal organ involvement. From a therapeutic perspective, several innovative strategies, including uPAR-targeting peptides, PAI-1 inhibitors, and molecules disrupting uPAR-FPR interaction, have shown encouraging antifibrotic efficacy in preclinical models. Summary: The fibrinolytic system has emerged as a central molecular hub linking SSc microvascular dysfunction, immune dysregulation, and fibrosis. Thus, restoring fibrinolytic homeostasis may offer a promising strategy to simultaneously improve angiogenesis, reduce fibrosis, and slow disease progression.