IGFBP5 is a multifunctional secreted protein that regulates insulin-like growth factor (IGF) availability and signaling in a cell-type-specific manner 1. It increases proliferation of osteoblasts and neuroblastoma cells while enhancing epithelial cell survival 2. IGFBP5 acts as a major mediator of mTORC1-dependent feedback inhibition of IGF1 signaling and promotes extracellular matrix production independently of IGF binding 34. Beyond IGF regulation, IGFBP5 functions as a ligand for ROR1 receptor, facilitating ROR1/HER2 heterodimer formation to enhance CREB oncogenic signaling 5. Disease relevance encompasses diabetic kidney disease, where IGFBP5 levels are significantly elevated and promote renal inflammation through PFKFB3-mediated endothelial glycolysis 6. In diabetic nephropathy, IGFBP5 drives endothelial-mesenchymal transition and renal fibrosis via NLRP3 inflammasome activation and histone lactylation 7. In glioblastoma, IGFBP5 promotes glioblastoma stem cell invasion through the ROR1/HER2-CREB axis 5. IGFBP5 supports hematopoietic stem cell expansion in fetal liver 8 and correlates with metabolic abnormalities in vitiligo 9. In breast cancer, estrogen-regulated IGFBP5 exhibits context-dependent effects as tumor suppressor or promoter 10. Clinical significance lies in IGFBP5's emerging role as a therapeutic target across inflammatory, fibrotic, and neoplastic diseases.