CEMIP2 (also known as TMEM2) is a cell-surface hyaluronidase that mediates the initial cleavage of high-molecular-weight hyaluronan into intermediate-size fragments of approximately 10-5 kDa 1. As a key regulator of systemic hyaluronan catabolism, CEMIP2 functions in extracellular matrix remodeling and is specifically active on hyaluronan, unable to cleave other glycosaminoglycans 2. CEMIP2 operates in physiological HA turnover across tissues including skin, lymph nodes, and liver 2. Mechanistically, CEMIP2 promotes ER homeostasis and stress resistance through CD44-dependent signaling involving ERK and p38 MAPK pathways, independent of canonical unfolded protein response activation 3. The protein is upregulated in response to UV irradiation in human epidermis 4. Clinically, CEMIP2 serves as a prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC) chemotherapy response 5. Elevated CEMIP2 expression enhances gemcitabine efficacy through HA degradation, improving drug delivery and vascular density while reprogramming the tumor microenvironment by modulating cancer-associated fibroblasts and immune cell populations 6. Additionally, CEMIP2 expression correlates with acute-on-chr9 liver failure progression and prognosis 7, positioning it as a potential therapeutic target in multiple diseases involving extracellular matrix dysfunction.