Authors
Miranda Türkal, Christine Maeder, Marta Correia de Sousa, Margot Fournier, Sanae El-Harane, Monika Gjorgjieva, Michelangelo Foti, Pierre Maecher, Etienne Delangre
Published in
EMBO molecular medicine. Jun 10, 2026. Epub Jun 10, 2026.
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.
PMID:
42271090
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.
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