KDELR3 is an endoplasmic reticulum (ER) retention receptor that binds the K-D-E-L C-terminal motif on ER-resident proteins and mediates their recycling from the Golgi back to the ER via COPI-coated vesicles 1. Beyond its canonical retrograde transport function, KDELR3 plays critical roles in regulating ER stress responses and the unfolded protein response (UPR). In lung adenocarcinoma, KDELR3 suppresses ER stress-induced apoptosis by inhibiting UPR pathway activation (PERK/EIF2α phosphorylation), promoting tumor growth and metastasis; this function is transcriptionally controlled by FOXM1 1. KDELR3 expression is significantly elevated in multiple malignancies including glioma and uveal melanoma, where it serves as an independent adverse prognostic indicator and correlates with immune cell infiltration 2, 3. In metabolic disease, a Kdelr3 mutation impairs pancreatic beta cell function and insulin granule maturation, contributing to type 2 diabetes susceptibility 4. KDELR3 is also dysregulated in non-malignant conditions including diabetic foot ulcers, osteoarthritis, and membranous nephropathy, where it functions as a diagnostic biomarker 5, 6, 7. During adipose-derived stem cell osteogenic differentiation, KDELR3 upregulation correlates with loss of stemness 8. These findings establish KDELR3 as a multifunctional protein linking ER homeostasis to disease pathogenesis across diverse tissues.