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Updated: Jun 12, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
S100A10-ANXA2 tetramer inhibition hampers hepatic stellate cell activation in human MASLD organoids
Miranda Türkal1,2, Christine Maeder1,2, Marta Correia de Sousa1,2
1Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Abstract:
Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), initiated by the pathological lipid accumulation within hepatocytes, can progress towards Metabolic dysfunction-Associated SteatoHepatitis (MASH) characterized by inflammation and fibrosis. Hepatic fibrosis is the strongest predictor of liver-related mortality, yet effective antifibrotic therapies remain limited, calling for identification of new molecular targets. Our previous work identified S100A10 as a MASLD promoter, suggesting that its association with AnnexinA2 (ANXA2) within the S100A10-ANXA2 heterotetramer (A2t) might promote hepatic fibrosis. Here, we inhibited A2t using its inhibitor, A2ti-1, in human hepatic stellate cells (LX-2) and in human multilineage liver organoids (HLOs) modeling MASLD. In LX-2, A2ti-1 reduced α-SMA protein levels and expression of profibrotic genes, indicating direct suppression of stellate cell activation. In HLOs, A2ti-1 significantly reduced fibrosis by lowering α-SMA levels, collagen deposition, and profibrotic gene expression, without altering steatosis. Mechanistically, A2ti-1 inhibited hepatic stellate cell activation through a SMAD-independent mechanism involving reduced STAT3 phosphorylation. These findings identify the S100A10-ANXA2 tetramer as a new regulator of hepatic stellate cells activation and highlight its inhibition as a promising antifibrotic strategy in MASH.
Insights
Inhibiting the S100A10-AnnexinA2 heterotetramer (A2t) with A2ti-1 reduces liver fibrosis in models of Metabolic dysfunction-Associated SteatoHepatitis (MASH). This novel antifibrotic strategy targets hepatic stellate cell activation without affecting steatosis.
Area of Science:
- Hepatology
- Molecular Biology
- Fibrosis Research
Background:
- Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) can progress to MASH, characterized by inflammation and fibrosis.
- Hepatic fibrosis is a major predictor of liver-related mortality, with limited antifibrotic therapies.
- The S100A10-AnnexinA2 heterotetramer (A2t) was previously identified as a potential promoter of MASLD and hepatic fibrosis.
Purpose of the Study:
- To investigate the role of the S100A10-AnnexinA2 heterotetramer (A2t) in promoting hepatic fibrosis.
- To evaluate the efficacy of the A2t inhibitor, A2ti-1, as an antifibrotic strategy in MASLD/MASH models.
Main Methods:
- Inhibition of A2t using A2ti-1 in human hepatic stellate cells (LX-2) and human liver organoids (HLOs) modeling MASLD.
- Assessment of stellate cell activation markers (e.g., α-SMA) and profibrotic gene expression.
- Analysis of collagen deposition and STAT3 phosphorylation.
Main Results:
- A2ti-1 treatment suppressed α-SMA protein levels and profibrotic gene expression in LX-2 cells, indicating direct inhibition of stellate cell activation.
- In HLOs, A2ti-1 significantly reduced fibrosis markers, including α-SMA and collagen deposition, without impacting steatosis.
- Mechanistically, A2ti-1 inhibited stellate cell activation via a SMAD-independent pathway involving reduced STAT3 phosphorylation.
Conclusions:
- The S100A10-AnnexinA2 tetramer (A2t) is a novel regulator of hepatic stellate cell activation.
- Inhibition of A2t by A2ti-1 represents a promising antifibrotic therapeutic strategy for MASH.
- Targeting A2t offers a new avenue for treating liver fibrosis in MASLD.