Abstract
OBJECTIVE: To systematically review the pleiotropic roles of Cathepsin K (CTSK) beyond classical bone resorption, elucidating its critical function in regulating extracellular matrix (ECM) dynamics and epithelial-mesenchymal transition (EMT) across diverse pathological systems. METHODS: A comprehensive analysis was conducted to synthesize the molecular architecture and signaling networks of CTSK, including the RANKL-RANK and NF-κB pathways. The review stratifies mechanistic and clinical evidence across five major domains: malignant tumors, cardiovascular diseases, pulmonary disorders, orthopedic conditions, and metabolic diseases, while evaluating the development and risks of CTSK inhibitors. RESULTS: CTSK acts as a versatile protease in ECM remodeling. In oncology, it facilitates metastasis in breast, gastric, and prostate cancers by degrading matrix barriers and activating EMT. In cardiovascular and pulmonary pathologies, CTSK exhibits a dualistic nature: it promotes atherosclerotic plaque instability and fibrosis progression but is protective in ischemic vascular remodeling. Furthermore, in metabolic disorders like T2DM and obesity, upregulated CTSK drives pathological collagen degradation, compromising tissue integrity. In orthopedic diseases, it is a key effector molecule responsible for bone matrix degradation and impaired tissue repair. Therapies targeting CTSK (such as inhibitors) show promise but raise safety concerns including off-target effects and increased stroke risk. CONCLUSION: CTSK is a central hub integrating upstream signals to regulate systemic ECM homeostasis, making it a promising therapeutic target. Future therapeutic strategies should focus on developing highly selective inhibitors to achieve precise regulation and balance efficacy with safety.