CSTA (cystatin A) is an intracellular and secreted thiol proteinase inhibitor with multifaceted roles in skin physiology and systemic health. In the epidermis, CSTA mediates desmosome-mediated cell-cell adhesion and keratinocyte differentiation through its protease-inhibitory activity 1. Beyond local skin function, CSTA acts as an epidermally-derived hormone: keratinocyte-secreted CSTA binds receptor for activated C-kinase 1 on osteoblast and osteoclast progenitors, promoting osteoblast proliferation while inhibiting osteoclast differentiation, thereby regulating bone metabolism 1. CSTA secretion decreases with skin aging, contributing to senile osteoporosis, and topical calcipotriol can stimulate CSTA production to alleviate this condition. In cancer biology, CSTA expression inversely correlates with metastatic potential. Low CSTA in nasopharyngeal carcinoma and oral squamous cell carcinoma associates with increased metastasis and poor survival 2 3. CSTA suppresses AKT signaling by promoting METTL3 degradation, reducing cancer cell motility 2. Genetically, CSTA variants at PSORS4 interact with HLA-C and other loci to confer over 100-fold increased psoriasis risk, indicating gene-gene interactions in inflammatory disease 4. CSTA also participates in DNA repair mechanisms, where it prevents Ku70 degradation to facilitate double-strand break repair in hepatocellular carcinoma 5, and modulates glycolytic metabolism in trabecular meshwork cells 6.