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S100A10-ANXA2 TETRAMER INHIBITION HAMPERS HEPATIC STELLATE CELL ACTIVATION IN MASLD MODELING HUMAN LIVER ORGANOIDS

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD), which begins with the pathological lipid accumulation within hepatocytes, can progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by inflammation and fibrosis. Fibrosis is the strongest predictor of liver-related mortality, yet effective antifibrotic therapies remain limited, underscoring the need for new molecular targets. Our previous work identified S100A10 as a MASLD promoter, suggesting that its association with Annexin A2 (ANXA2) within the S100A10-ANXA2 heterotetramer (A2t) might promote hepatic fibrosis. Here, we inhibited A2t using its specific inhibitor, A2ti-1, in human hepatic stellate cells (LX-2) and in human multilineage liver organoids (HLOs) modeling MASLD. A2ti-1 reduced α-SMA protein levels and decreased expression of profibrotic genes in LX-2 cells by directly suppression of stellate cell activation. In HLOs, A2ti-1 significantly attenuated fibrosis by reducing α-SMA expression, collagen deposition, and profibrotic genes, without altering steatosis. Mechanistically, A2ti-1 inhibited LX-2 activation through reducing STAT3 phosphorylation independently of SMAD signaling. These findings identify A2t as a previously unrecognized regulator of hepatic fibrosis and establish its pharmacological inhibition as a promising antifibrotic therapeutic strategy in MASH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313271 | GEO | 2026/04/16

REPOSITORIES: GEO

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Project description:P7C3, an aminopropyl carbazole compound with established neuroprotective properties and therapeutic potential in neurodegenerative disorders, has demonstrated broad pharmacological activity across multiple pathologies. However, the effect of P7C3 on hepatic fibrosis remains unexplored. This research applied in vitro and in vivo systems to evaluate P7C3's antifibrotic efficacy. The findings demonstrated that P7C3 notably inhibited the proliferation of LX-2 cells and decreased the levels of the fibrotic markers collagen type alpha 1 (COL1A1) and fibronectin (FN). Eukaryotic initiation factor 4A1 (eIF4A1) was identified as a direct target of P7C3 through the integration of cellular thermal shift assay (CETSA) coupled with mass spectrometry and human protein microarray data, and subsequently validated using CETSA, drug affinity responsive target stability, and molecular docking analysis. P7C3 treatment markedly inhibited eIF4A1 levels in LX-2 cells, while eIF4A1 knockdown attenuated this effect by suppressing COL1A1 and FN expression. Mechanistically, P7C3 impaired global protein synthesis in hepatic stellate cells, including c-Myc, consistent with the outcomes observed following eIF4A1 silencing. Both eIF4A1 knockdown and P7C3 treatment significantly downregulated ULK1, induced accumulation of autophagic substrate p62, and increased LC3B-II/LC3B-I ratio, indicating potent disruption of autophagic flux via eIF4A1 targeting. Histopathological assessment of the liver tissues revealed that P7C3 significantly attenuated collagen deposition and architectural distortion in fibrotic mice. Concomitant improvements were observed in the hepatic function biomarkers, including serum ALT and AST levels, as well as in fibrotic markers (hydroxyproline content). Collectively, these findings delineate eIF4A1 as the primary target through which P7C3 alleviates hepatic fibrosis by suppressing protein translation and autophagic flux, providing mechanistic validation for advancing P7C3 as a promising antifibrotic agent.

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S100A10-ANXA2 TETRAMER INHIBITION HAMPERS HEPATIC STELLATE CELL ACTIVATION IN MASLD MODELING HUMAN LIVER ORGANOIDS

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