Tryptase-like proteases, a subset of serine proteases predominantly released from mast cells, are gaining attention as key contributors to fibrosis, offering a novel perspective on the mechanisms driving chronic tissue scarring. Fibrosis, characterized by excessive extracellular matrix (ECM) deposition and organ dysfunction, has long been attributed to persistent inflammation and aberrant wound healing, yet emerging evidence highlights the role of mast cell–derived mediators in amplifying fibrotic responses.
Among them, tryptase-like proteases exert profound effects by activating protease-activated receptors (PARs), especially PAR-2, on fibroblasts and other stromal cells, thereby initiating signaling cascades that enhance fibroblast proliferation, myofibroblast differentiation, and collagen production. This activity not only accelerates ECM accumulation but also disrupts the balance between matrix synthesis and degradation, perpetuating a fibrotic microenvironment.
Studies in pulmonary, hepatic, renal, and cardiac fibrosis models suggest that tryptase activity drives disease progression across multiple organ systems, underscoring its broad pathological significance. Importantly, pharmacological strategies targeting tryptase-like proteases, including specific inhibitors and PAR antagonists, have shown promise in reducing collagen deposition and mitigating fibrotic severity in preclinical settings, suggesting therapeutic potential.
Furthermore, elevated levels of these proteases may serve as valuable biomarkers for early detection and monitoring of fibrotic diseases. By reframing mast cell proteases from their classical roles in allergy to central players in fibrosis, researchers can uncover new molecular pathways for intervention. Thus, tryptase-like proteases not only deepen our understanding of fibrogenesis but also represent innovative targets for the development of anti-fibrotic therapies in chronic and progressive disorders.