# Integrin β3 Orchestrates Hepatic Steatosis via a Novel CD36‐Dependent Lipid Uptake Complex

## TL;DR

This study shows how a protein called ITGB3 worsens liver disease by increasing fat uptake, and suggests targeting ITGB3 could be a new treatment for MASH.

## Contribution

The paper reveals a novel ITGB3-dependent mechanism that enhances CD36-mediated fatty acid uptake in MASH.

## Key findings

- ITGB3 overexpression in hepatocytes worsens diet-induced obesity, insulin resistance, steatosis, and fibrosis in mice.
- Pharmacologic inhibition of ITGB3 improves serum lipid profiles and hepatic steatosis.
- ITGB3 promotes CD36 palmitoylation and fatty acid uptake via a complex with DHHC5 and LYN.

## Abstract

In metabolic dysfunction‐related steatohepatitis (MASH), ITGB3 promotes hepatic fibrosis via activating hepatic stellate cells, but whether it directly regulates hepatic lipid metabolism through membrane‐scaffolding function and the underlying mechanisms remain unclear. Transcriptomic analyses of human and murine models of MASH revealed consistent upregulation of ITGB3 in hepatocytes. In mice, the hepatocyte‐specific overexpression of ITGB3 exacerbates diet‐induced obesity, insulin resistance, steatosis, and fibrosis, the deletion of ITGB3 alleviates these phenotypes. Additionally, the overexpression of DHHC5 reversed the hallmarks of MASH in ITGB3‐deficient mice, confirming the central role of DHHC5 in this process. Mechanistically, ITGB3 is a novel “accelerator” that directly increases CD36‐mediated fatty acid uptake by recruiting LYN, then modulating LYN protein stability, and triggering LYN proteasomal degradation. This degradation relieves LYN–mediated inhibition of DHHC5 and promotes ITGB3/DHHC5/CD36 complex formation, thereby enhancing DHHC5‐dependent CD36 palmitoylation and subsequent CD36‐mediated fatty acid uptake. Pharmacologic inhibition of ITGB3 using cyclic‐RGDfk peptide improved serum lipid profiles and hepatic steatosis. This study uncovers a previously unrecognized mechanism by which ITGB3 acts as a driver of hepatic steatosis of hepatic steatosis. Targeted intervention against ITGB3 to modulate CD36‐mediated lipid uptake may represent a novel therapeutic strategy for the treatment of MASH.

In MASH, ITGB3 recruits LYN and drives its ubiquitin‐proteasomal degradation via phosphorylation. This relieves DHHC5 inhibition, enabling ITGB3/DHHC5/CD36 complex assembly to enhance CD36 palmitoylation and fatty acid uptake, thereby exacerbating disease. Targeting ITGB3 blocks this pathogenic axis and ameliorates MASH.