S100A10-ANXA2 tetramer inhibition hampers hepatic stellate cell activation in human MASLD organoids

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.