IGFBP6 (Insulin Like Growth Factor Binding Protein 6)

We conclude by identifying key knowledge gaps, methodological limitations, and priorities for future studies, including standardized measurement, cell-type-resolved profiling, and in vivo perturbation in clinically relevant models. Collectively, the review positions IGFBP-6 as a nuanced regulator of liver pathophysiology and a promising, yet underexplored, lever for diagnosis and therapy.

Knockdown of IGFBP-6 in a Triple Negative breast cancer cell line, MDA-MB-231, also resulted in a decrease in Cyclin B1 accumulation demonstrating that our observations are not cell line specific. Taken together, our results demonstrate that IGFBP-6 regulates cell cycle progression in breast cancer cells and interferon signaling in hormone positive cells.

scRNA-seq analysis indicated that HSD17B1 was predominantly expressed in epithelial cells and was significantly involved during their malignant transformation (confirmed by ST). This study identified HSD17B1 as a critical target gene for genistein in GA treatment, emphasizing its roles in the malignant transformation of epithelial cells, thus providing a theoretical foundation for understanding the therapeutic mechanism of genistein in GA.

The results of this study indicate that the reduction in cholesterol levels observed in breast cancer cells following IGFBP6 knockdown is primarily due to decreased exogenous uptake. These findings highlight the role of IGFBP6 in regulating cholesterol metabolism and further explain its clinical significance in predicting breast cancer recurrence and progression.

This review examines the growing understanding of IGFBP-6 beyond its classical role as an IGF-binding protein, with a focus on its involvement in redox homeostasis. By exploring these emerging roles, we aim to elucidate how IGFBP-6 contributes to redox homeostasis and to assess its potential as a therapeutic target in oxidative stress-related diseases, including fibrosis, cancer, and immune dysfunction.

IGFBP-6 effectively inhibits IGF-2-induced effects but has no impact on Des(1-6)IGF-2, highlighting the latter's ability to evade IGFBP-mediated inhibition due to structural modifications. These results suggest that Des(1-6)IGF-2 may serve as a potent pro-angiogenic agent with therapeutic potential, while IGFBP-6 could offer a strategy for suppressing pathological angiogenesis.

This study underscored the utility of combining machine learning feature selection with survival analysis to enhance prognostic modelling while balancing predictive performance and interpretability.

Interestingly, our kinetic analysis of ferroptosis induction showed that IGFBP6 knockdown cells began to die earlier and could hardly be rescued from erastin-induced ferroptosis by mitochondrial antioxidant SkQ1, in contrast to control cells. Overall, our data suggest that the action of DHA is less dependent on mitochondrial membrane peroxidation during ferroptosis induction and this molecule can be a promising candidate for the treatment of breast cancer, especially in the case of reduced IGFBP6 gene expression in cancer cells.

Exploring essential prognostic-risk genes and their association with the prognosis, diagnostic efficacy, and risk-group prediction may provide substantial clues for targeting the breast cancer stromal key-risk genes.

The ferroptosis-based risk model provides valuable prognostic insights into GBM and highlights potential therapeutic targets, emphasizing the biological significance of ferroptosis-related genes in tumor progression.

Finally, IGFBP6-deficient mice show aggravated diet- and DF-induced atherosclerosis, whereas endothelial-cell-specific IGFBP6-overexpressing mice protect against atherosclerosis. Based on these findings, we propose that reduction of endothelial IGFBP6 is a predisposing factor in vascular inflammation and atherosclerosis, which can be therapeutically targeted.

Stable overexpression of IGFBP-6 in MCF-7 cells resulted in an increase in Epidermal Growth Factor Receptor (EGFR) and this expression was further enhanced when cells were cotreated with progesterone and estradiol. These results indicate that IGFBP-6 is a regulator of progesterone action, and that PR is required for the observed protective effects of IGFBP-6 in breast cancer.