# Myeloid-Specific STAT3 Deletion Aggravates Liver Fibrosis in Mice Fed a Methionine- and Choline-Deficient Diet via Upregulation of Hepatocyte-Derived Lipocalin-2

## TL;DR

Deleting STAT3 in myeloid cells worsens liver fibrosis in mice on a diet lacking methionine and choline by increasing lipocalin-2 in liver cells.

## Contribution

This study reveals a compensatory STAT3/LCN2 axis in hepatocytes that exacerbates MASH when myeloid STAT3 is deleted.

## Key findings

- Myeloid-specific STAT3 deletion increased liver fibrosis in MCD diet-fed mice despite reduced lipid accumulation.
- mSTAT3KO mice showed elevated hepatocyte STAT3 and LCN2 levels, along with increased inflammation and apoptosis.
- MCD diet-induced proteins like CD36 and perilipin-2 were reduced in mSTAT3KO mice.

## Abstract

The signal transducer and activator of transcription 3 (STAT3) in myeloid cells suppresses proinflammatory cytokine production and reduces collagen deposition. However, its role in methionine- and choline-deficient (MCD) diet-fed mice remains unclear. This study investigates the effects of myeloid-specific STAT3 deficiency on hepatic inflammation and fibrosis in MCD diet-fed mice. Myeloid-specific STAT3 knockout (mSTAT3KO) mice were fed the MCD diet for four weeks to induce metabolic dysfunction-associated steatohepatitis (MASH). MCD diet-fed mice displayed MASH-like pathological phenotypes, including hepatic steatosis, inflammation, and fibrosis. Compared with MCD diet-fed WT mice, mSTAT3KO mice fed the MCD diet exhibited reduced hepatic lipid accumulation but increased fibrosis. Notably, mSTAT3KO mice showed elevated hepatic STAT3 and lipocalin-2 (LCN2) protein levels in hepatocytes. Some proinflammatory cytokines were increased by the MCD diet in mSTAT3KO mice, which also exhibited increased hepatocyte apoptosis. Conversely, MCD diet-induced CD36, perilipin-2, acyl-CoA thioesterase 2, and 4-hydroxynonenal proteins were reduced by mSTAT3KO. Myeloid-specific STAT3 deficiency may induce a compensatory STAT3/LCN2 axis in hepatocytes, thereby exacerbating MASH progression.