KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which serves as a membrane receptor that binds the KDEL sequence motif in ER-resident proteins and maintains their localization through vesicle-mediated recycling from the Golgi back to the ER 1. The receptor functions in pH-dependent manner and participates in COPI retrograde transport 1. KDELR2 plays a critical role in collagen metabolism by interacting with HSP47, a molecular chaperone essential for collagen type I folding 1. Bi-allelic pathogenic variants in KDELR2 cause osteogenesis imperfecta type XXI by disrupting the KDELR2-HSP47 interaction, leading to HSP47 remaining bound to collagen extracellularly and disrupting fiber formation 12. Beyond its classical ER function, KDELR2 exhibits oncogenic properties in multiple cancers. It promotes tumor progression through cell cycle regulation, particularly by protecting centrosomal protein POC5 from degradation and regulating CCND1 expression 34. KDELR2 enhances cancer cell proliferation, invasion, and metastasis by promoting Golgi-mediated secretion, including matrix metalloprotease secretion 5. In respiratory disease, KDELR2 contributes to COPD pathology by regulating MUC5AC mucin hypersecretion through IRE1α/XBP-1s signaling pathways 6. High KDELR2 expression correlates with poor prognosis across multiple cancer types 47.