Multidirectional therapeutic effects of synthesized HMGB1 peptide on liver cirrhosis in mice

TL;DR

A synthesized HMGB1 peptide shows multiple therapeutic effects in reducing liver cirrhosis in mice by targeting fibrosis and improving liver cell function.

Contribution

The study demonstrates the multidirectional effects of HMGB1 peptide treatment on liver cirrhosis, including fibrosis reduction and improved lipid metabolism.

Findings

HMGB1 peptide treatment reduces αSMA-positive hepatic stellate cells from week two in a cirrhosis model.

Treatment suppresses collagen pathway activity in macrophages and enhances hepatocyte lipid metabolism.

Peptide treatment induces cell migration factors like Cxcl12 and Ccl25, suggesting enhanced liver healing.

Abstract

Liver cirrhosis is a serious disease characterized by liver dysfunction and severe fibrosis; however, no breakthrough drugs have effectively improved fibrosis, making it an unmet medical need. We have previously reported that the HMGB1 peptide, synthesized from box A of the HMGB1 protein, ameliorates liver fibrosis and is a promising candidate for fibrosis-improving drugs against liver cirrhosis. In this study, we used spatial analysis to observe treatment-induced changes over time.

Liver cirrhosis was induced in C57BL/6J mice using carbon tetrachloride (CCl4) injections, followed by HMGB1 peptide treatment. To assess the temporal effects of HMGB1 on the liver in a CCl4-induced cirrhosis mouse model, we used GeoMx spatial analysis. We focused on αSMA-positive active hepatic stellate cells (HSCs), F4/80-positive macrophages, and CK8/18-positive hepatocytes to determine how each cell type was affected over time. Statistical analyses were conducted using GraphPad Prism9, with significance set at p < 0.05.

In cirrhotic mice, we first observed a decrease in the number of activated HSCs over time, two weeks after treatment initiation. Macrophage-associated genes ceased to induce fibrosis-related pathways early in the treatment. This suggests that the effect of macrophages on fibrosis was weakened by the treatment. We also confirmed that lipid metabolism of hepatocytes may be improved during treatment. Furthermore, Cxcl12 and Ccl25 expression were induced in the peptide-treated group, indicating possible cell migration to the liver.

Over time, macrophages followed by HSCs, showed the most notable changes with treatment, resulting in improved fibrosis. The HMGB1 peptide drug also affected lipid metabolism in hepatocytes, suggesting a positive therapeutic effect on steatohepatitis. Elevated factors that promote cell migration may have also enhanced the healing effect.

•HMGB1 peptide treatment reduces αSMA-positive cells from week two in cirrhosis model.•Control group shows collagen pathway activity; not seen in treated group.•Treatment enhances lipid metabolism in hepatocytes.•GPCR ligand binding detected in both macrophages and hepatocytes.•Treatment may reduce liver injury and fibrosis via multiple pathways.

HMGB1 peptide treatment reduces αSMA-positive cells from week two in cirrhosis model.

Control group shows collagen pathway activity; not seen in treated group.

Treatment enhances lipid metabolism in hepatocytes.

GPCR ligand binding detected in both macrophages and hepatocytes.

Treatment may reduce liver injury and fibrosis via multiple pathways.

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