It’s a Trap!—Potential of Cathepsins in NET Formation

Neutrophils are first-line immune effectors in innate immunity, employing migration, phagocytosis, and neutrophil extracellular trap (NET) formation to combat infections and mediate inflammatory responses. NET formation, the regulated extrusion of chromatin and antimicrobial proteins, is crucial for pathogen clearance but can lead to pathological inflammation when dysregulated. Cathepsins, a diverse family of proteolytic enzymes traditionally associated with lysosomal protein degradation, have emerged as key modulators of neutrophil functions. Serine cathepsins, including cathepsin G, and cysteine cathepsins, such as cathepsin C, regulate neutrophil migration, chemokine processing, and serine protease maturation, thereby orchestrating effective phagocytosis and antimicrobial activity. These enzymes also influence NET formation, linking classical lysosomal proteolysis to specialized immune responses. This review synthesizes current evidence on cathepsin-mediated regulation of neutrophil effector functions, highlighting their dual role in host defense and disease pathology, and discusses their potential as therapeutic targets for mitigating NET-driven inflammation in conditions such as autoimmune diseases, cancer metastasis, and ischemia-reperfusion injury.