RCN1 (reticulocalbin 1) is a calcium-binding protein localized to the endoplasmic reticulum (ER) lumen that regulates calcium-dependent activities and ER homeostasis 1. Mechanistically, RCN1 modulates ER stress responses through its EF-hand calcium-sensing domains, which fine-tune binding to inositol 1,4,5-trisphosphate receptor 1 (IP3R1) to regulate ER-mitochondria calcium transfer and coupling 2. RCN1 expression is aberrantly elevated in multiple malignancies including acute myeloid leukemia, esophageal squamous cell carcinoma, and colorectal cancer, where it associates with poor prognosis and metastatic potential 345. In disease contexts, RCN1 dysregulation drives pathological outcomes: downregulation promotes AML cell pyroptosis through caspase-1/GSDMD signaling 3; reduced RCN1 in diabetic endothelium impairs angiogenesis and ulcer healing via ER stress intensification 1; and elevated RCN1 in keloids promotes fibroblast proliferation and collagen production via IRE1α-XBP1 ER stress activation 6. Conversely, RCN1 acts as an ER stress biomarker in multiple sclerosis 7. These findings identify RCN1 as a context-dependent therapeutic target: inhibition benefits cancer and keloid treatment, while restoration improves diabetic wound healing.