NUCB1 is a multifunctional calcium-binding protein with diverse cellular and physiological roles. As a major Golgi calcium-binding protein, NUCB1 participates in calcium homeostasis and functions as a non-receptor guanine nucleotide exchange factor for G-protein signaling 1. Beyond these intracellular roles, NUCB1 serves as a secreted protein that can be rapidly exported from the endoplasmic reticulum via SEC24C/D-dependent mechanisms 2. NUCB1 exhibits multidomain functionality, including RNA-binding and RNA-melting activities, and acts as a transcription factor binding E-box motifs 3. The protein contains bioactive peptide sequences; notably, NUCB1 encodes a nesfatin-1-like peptide (NLP) that suppresses feed intake and stimulates insulin secretion 1. In cancer pathophysiology, tumor-derived INSL3 upregulates hypothalamic NUCB1 to induce cancer-associated anorexia by regulating feeding neuropeptides 4. NUCB1 expression is significantly elevated in colorectal adenocarcinoma, correlating with clinical stage, differentiation, and lymphatic metastasis 5. Additionally, elevated NUCB1 levels in cerebrospinal fluid associate with depression in HIV-infected patients 6. NUCB1 stability is regulated through CHIP-mediated proteasomal and non-proteasomal degradation pathways involving Hsp70 7, suggesting its importance in osteoblast differentiation and bone formation.