Cathepsin S (CTSS) is a lysosomal cysteine protease with dual roles in immune function and extracellular matrix remodeling 1. As a thiol protease, CTSS mediates antigen processing by cleaving the invariant chain from MHC class II molecules, facilitating antigen presentation 1. Beyond immune regulation, CTSS functions as a secreted protease in extracellular environments. Macrophage-derived CTSS promotes liver fibrogenesis by cleaving collagen 18A1 to release endostatin, which activates hepatic stellate cells via integrin signaling 2. Piezo1-regulated CTSS secretion in macrophages drives inflammatory responses contributing to hepatic fibrosis progression 3. In peripheral nerve regeneration, M2 macrophage-derived CTSS cleaves Ephrin-B2 in fibroblasts to activate Schwann cell repair programs 4. Pathologically, neuronal CTSS elevation promotes neuroinflammation and cognitive decline in aging and Alzheimer's disease through CX3CL1-CX3CR1 and JAK2-STAT3 pathways 5. In cardiovascular disease, stress-induced CTSS elevation increases thrombosis risk via inflammation and oxidative stress mechanisms 6. Recent evidence identifies CTSS as a ferroptosis regulator in hepatocellular carcinoma, where it protects cancer cells by degrading KEAP1 and activating NRF2 antioxidant pathways 7. CTSS inhibition shows therapeutic promise across fibrotic, neurodegenerative, cardiovascular, and malignant diseases.