Osteopontin: a central hub in the pathogenesis and therapeutic intervention of liver disease

Osteopontin (OPN) is a phosphorylated glycoprotein implicated in inflammation and tissue remodeling. Its expression is significantly elevated in various liver diseases, but its precise pathophysiological roles remain complex and context-dependent.

This review systematically examines the mechanisms of OPN in multiple liver diseases, including acute liver injury, alcoholic liver disease, viral hepatitis, metabolic-associated fatty liver disease, and hepatocellular carcinoma. It focuses on its cell-type-specific functions and explores its potential as a diagnostic biomarker and therapeutic target.

OPN exhibits a dual role in liver pathophysiology. It promotes disease progression by activating hepatic stellate cells to drive fibrosis, enhancing collagen deposition, and facilitating HCC invasion and metastasis. Conversely, OPN also demonstrates protective functions. Intestinal OPN preserves gut barrier integrity and microbiome homeostasis, ameliorating alcohol-induced liver injury. Notably, a recent identified mechanism reveals that macrophage-derived OPN activates the OSM-STAT3-ARG2 signaling axis in hepatocytes, enhancing fatty acid oxidation and attenuating hepatic steatosis in MAFLD. Furthermore, OPN shows promise as a clinical biomarker for detecting early-stage HCC and assessing liver fibrosis, potentially outperforming alpha-fetoprotein.

Osteopontin serves as a central signaling hub in liver diseases, where it effectively integrates inflammatory, metabolic and fibrogenic networks. Harnessing its therapeutic potential represents the cornerstone for developing future OPN-targeted therapies. This strategic approach will create new avenues for liver disease treatment, enabling precise interventions tailored to specific disease contexts.