# Insulin Growth Factor Binding Protein-6 and the Liver

## TL;DR

IGFBP-6 is a complex regulator in liver biology, influencing IGF-II availability and liver disease processes, with potential as a biomarker and therapeutic target.

## Contribution

This review identifies IGFBP-6 as a context-dependent regulator in liver pathophysiology with IGF-dependent and -independent roles.

## Key findings

- IGFBP-6 controls IGF-II availability and has IGF-independent actions in liver compartments like stellate and cancer-associated fibroblasts.
- Disease states and liver cancers dynamically regulate IGFBP-6 abundance and function through profibrotic, inflammatory, and metabolic cues.
- IGFBP-6 shows tumor-suppressive and pro-migratory roles in liver cancers, with potential for biomarker and therapeutic applications.

## Abstract

What are the main findings?

IGFBP-6 is a context-dependent regulator in the liver—enriched in stellate/cancer-associated fibroblast (CAF) compartments and shaped by lobular zonation—controlling IGF-II availability and exerting IGF-independent actions.

Profibrotic, inflammatory, hypoxia/redox, and metabolic cues (including PTMs like O-GlcNAc) dynamically tune IGFBP-6 abundance and function across disease states and liver cancers.

What are the implications of the main findings?

Research and clinical assays should shift from bulk abundance to function + location—PTM-aware proteomics, extracellular-vesicle profiling, and spatial readouts—to correctly interpret IGFBP-6 and IGF-II activity.

Translational strategies include composite biomarkers and patient selection frameworks that use total/modified IGFBP-6 to guide IGF-axis therapies or microenvironment-targeted approaches.

The insulin-like growth factor (IGF) axis orchestrates hepatic development, regeneration, and metabolism, yet the roles of individual IGF-binding proteins (IGFBPs) remain incompletely defined. IGFBP-6, a high-affinity, IGF-II-preferring binding protein, has emerged as a context-dependent modulator of IGF bioavailability and cell signaling with additional IGF-independent actions. This review synthesizes current evidence on IGFBP-6 in liver biology and disease. We first outline hepatic expression, regulation, and post-translational processing of IGFBP-6 across development, homeostasis, and injury, and summarize its effects on canonical IGF-II/IGF1R signaling and downstream phosphatidylinositol 3-kinase—protein kinase B (PI3K–AKT) and rat sarcoma—mitogen-activated protein kinase (RAS–MAPK) pathways. We then evaluate experimental and clinical data linking IGFBP-6 to steatotic liver disease, inflammation, and fibrogenesis, including putative roles in hepatocyte stress responses, stellate cell activation, and extracellular matrix remodeling. Finally, we examine IGFBP-6 in primary liver cancers—hepatocellular carcinoma and cholangiocarcinoma—highlighting evidence for tumor-suppressive versus pro-migratory activities, potential crosstalk with hypoxia, Wnt/β-catenin and TGF-β signaling, and interactions with the tumor immune microenvironment. Across conditions, we assess the translational potential of IGFBP-6 as a circulating or tissue biomarker, its utility for patient stratification, and prospects for therapeutic targeting—either by modulating IGF-II sequestration or exploiting IGF-independent mechanisms. 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.