CSTB (cystatin B) is an intracellular cysteine proteinase inhibitor that reversibly binds and inhibits cathepsins L, H, and B. Located on chromosome 21, CSTB functions as a negative regulator of proteolysis and is distributed across multiple cellular compartments including the cytoplasm, nucleus, and extracellular regions 1. The primary disease association is Unverricht-Lundborg disease (progressive myoclonus epilepsy type 1), caused by dodecamer repeat expansions in the CSTB promoter that dramatically reduce gene expression 2. CSTB-deficient models reveal diverse pathogenic mechanisms beyond protease inhibition, including altered glial activation, oxidative stress regulation, and neuronal hyperexcitability 1. Recent gene replacement therapy using AAV9-delivered CSTB in knockout mice significantly improved neuroinflammatory markers, cerebellar apoptosis, and motor function, supporting therapeutic potential 2. Beyond neurological disease, CSTB emerges as a hub gene in metabolic and infectious contexts. It was identified as one of three hub genes shared between sarcopenia and type 2 diabetes pathogenesis 3. In pancreatic cancer, CSTB orchestrates autophagy and glycolysis by sustaining cathepsin B proteolytic activity, promoting tumor cell survival 4. CSTB expression is significantly decreased during Zika virus placental infection, correlating with increased inflammation and fetal transmission 5. Additionally, elevated plasma CSTB following aerobic exercise training correlates with improved cognitive performance in adults at Alzheimer's disease risk 6.