Igfbp6, a member of the IGF binding protein (IGFBP) family, is a specific inhibitor of insulin-like growth factor II (IGF-II) [3]. It is involved in multiple biological processes, such as regulation of cell growth, apoptosis, migration, and immune-escape, and is associated with pathways like PI3K-Akt, TGF-β, and sonic hedgehog (SHH) signaling [3,4].

In endothelial cells, IGFBP6 suppresses vascular inflammation and atherosclerosis. IGFBP6-deficient mice show aggravated diet-and disturbed flow (DF)-induced atherosclerosis, while endothelial-cell-specific IGFBP6-overexpressing mice are protected against atherosclerosis, indicating its role in maintaining vascular homeostasis [1]. In esophageal squamous cell carcinomas, MAFB promotes malignant phenotypes by upregulating IGFBP6 [2]. In glioblastoma, lactate modulates microglia polarization via IGFBP6 expression, remodeling the tumor microenvironment [4]. In varicose veins, knocking down IGFBP6 in vascular smooth muscle cells (VSMCs) attenuates cell proliferation and affects cell morphology [5]. In glioma, overexpression of IGFBP6 induces apoptosis and inhibits migration, and it can be an independent prognostic factor [6]. In nasopharyngeal carcinoma, IGFBP6 may be an independent prognostic biomarker, as exogenous expression inhibits cell proliferation and invasion, and knockdown activates the GSK3β/β-catenin/cyclin D1 pathway [7]. In breast cancer, IGFBP6 is associated with prognosis, especially in patients without type 2 diabetes (T2D), and its upregulation increases drug sensitivity [3]. Also, knockdown of IGFBP6 in breast cancer cells leads to changes in lipid metabolism and increases sensitivity to ferroptosis [8].

In conclusion, IGFBP6 plays essential roles in regulating cell-related functions and is involved in various disease conditions, including atherosclerosis, multiple types of cancers, and varicose veins. The use of gene knockout (KO) or conditional knockout (CKO) mouse models, as well as in vitro loss-of-function experiments, has significantly contributed to understanding the role of IGFBP6 in these biological processes and diseases, providing potential therapeutic targets.