IGFBP6 (insulin-like growth factor binding protein 6) functions as a multifaceted signaling regulator that extends beyond traditional IGF binding to modulate diverse cellular processes. The protein binds IGF-I and IGF-II to regulate their bioavailability and receptor interactions 1. Importantly, IGFBP6 executes IGF-independent functions through direct protein-protein interactions, including binding to prohibitin-2 (PHB2) to regulate STAT1-mediated immune responses 2 and interacting with early growth regulator 1 (EGR1) to control fibrotic gene expression 3. The protein demonstrates tissue-specific roles in pathological processes. In vascular disease, endothelial IGFBP6 suppresses inflammation and atherosclerosis through the MVP-JNK/NF-κB signaling pathway 4. Conversely, IGFBP6 promotes pathological fibrosis in cardiac tissue by enhancing the EGR1-MFAP4 axis and fibroblast-to-myofibroblast transition 3, and drives hepatic fibrosis through TGF-β/SMADs pathway activation 5. In cancer contexts, IGFBP6 facilitates tumor progression by modulating immune cell polarization and metabolic reprogramming 1. Clinical studies identify IGFBP6 as a diagnostic biomarker for unstable atherosclerotic plaques 6 and glioblastoma prognosis 7, with altered expression levels correlating with disease severity across multiple conditions.