IGFBP3 is a multifunctional tumor suppressor that regulates insulin-like growth factor (IGF) signaling and exhibits independent antiproliferative effects. Primary function: IGFBP3 sequesters IGF1 and IGF2, limiting their receptor availability and suppressing IGF-mediated proliferation and promoting apoptosis 1. Beyond IGF regulation, IGFBP3 mediates cell growth inhibition through its receptor TMEM219/IGFBP-3R and the LRP-1 receptor via IRS1/IRS2 dephosphorylation 23. Nuclear IGFBP3 interacts with transcription factors like RXRA to regulate apoptotic signaling 1. Mechanism: IGFBP3 additionally regulates mitophagy through mTOR signaling under hyperosmolar stress 4 and mediates mitochondrial quality control in epithelial tissues. Recent evidence suggests IGFBP3 stabilizes PPAR-γ through deubiquitination, suppressing hepatocellular carcinoma progression 5. Disease relevance: IGFBP3 promoter methylation occurs in 63.8% of colorectal cancers and associates with lymph-node metastasis and poor survival 6. Specific polymorphisms (rs2854746) increase colorectal cancer susceptibility 7. In melanoma, epigenetic IGFBP3 repression by Snail2-HDAC3 complex promotes metastasis via PI3K-AKT pathway dysregulation 8. Clinical significance: IGFBP3 promoter methylation status serves as a prognostic biomarker, particularly in stage II colorectal cancer, with unmethylated status conferring improved survival outcomes.