CRELD2 (Cysteine-Rich with EGF-Like Domains 2) functions as an endoplasmic reticulum (ER) stress-inducible secretory protein with diverse physiological roles. Its primary function involves protein disulfide isomerase activity and regulation of cellular stress responses 1. CRELD2 expression and secretion are dramatically induced by ER stress through the PERK-ATF4 pathway, suggesting its crucial role in the unfolded protein response 12. The protein serves multiple tissue-specific functions: it regulates α4β2 nicotinic acetylcholine receptor expression by interacting with their large cytoplasmic domains and impairing membrane transport 3, acts as an angiogenic growth factor promoting ischemic heart repair after myocardial infarction 4, and functions as an adipokine involved in adipocyte differentiation 5. CRELD2's secretion is regulated by V-ATPase-mediated intravesicular acidification and requires Golgi apparatus transport 6. The gene exhibits extensive alternative splicing producing multiple isoforms with tissue-specific expression patterns 7. Clinically, CRELD2 is associated with various pathological conditions including cardiovascular diseases, kidney diseases, cancer, and chr22 liver diseases, particularly those involving ER stress 12. Its role in promoting malignant progression through TGF-β/SMAD and NF-κB pathway activation makes it a potential therapeutic target 2.