Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents progression of MASLD

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute to the development of MASLD, however, the role of the Unc-51-like autophagy-activating kinase 1 (ULK1) in the pathophysiology of MASLD remains unclear. Herein, we show that ULK1, a serine/threonine kinase and core autophagy protein, is significantly repressed in human MASH livers, and that hepatocyte-specific loss of ULK1, unexpectedly, promotes hepatic steatosis and progression to liver fibrosis, without affecting basal autophagy flux. Phospho-proteomics identified the transcriptional coactivator NCOA3 as a downstream phospho-target of ULK1. Mechanistically, ULK1 phosphorylates NCOA3 to repress its transcriptional activity and restrain the CREB/CBP-mediated de novo lipogenic program. Accordingly, a phosphorylation-deficient NCOA3 mutant drives CREB/CBP-mediated lipogenesis, whereas genetic or pharmacological NCOA3 inhibition prevents steatosis, hepatic inflammation, and profibrotic signaling. Hence, ULK1-mediated NCOA3 phosphorylation is a fundamental and druggable checkpoint against the entire MASLD spectrum.

2026-03-26 | PXD072418 | Pride

Gene expression profile at single cell level of hepatocytes and non parenchymal cells (NPCs) isolated from a murine model of MASLD

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) embraces different conditions, including metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The landscape of cellular abnormalities occurring in the different stages of MASLD as well as the processes which drive MASLD evolution are not completely clarified. We used single cell RNAsequencing (scRNAseq) to unravel cellular heterogeneity affecting livers during the switching from simple steatosis towads MASH and and MASH-fibrosis.

2025-02-28 | GSE284186 | GEO

Peroxisome Proliferator-activated Receptor Agonist IVA337 Alleviates Inflammation

Project description:Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by significant hepatic fibrosis and inflammation. The pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist IVA337 (lanifibranor) has demonstrated potential as an anti-MASH therapeutic, although its mechanisms of action remain incompletely understood. This study explores the effects and mechanisms of IVA337 using two distinct MASH models: 2D primary human hepatic stellate cells (HSCs) stimulated with TGFß1, and 3D liver spheroids comprising primary hepatocytes, HSCs, and nonparenchymal cells. In TGFß1-stimulated HSCs, IVA337 effectively suppressed the expression of fibrosis-related genes, including PAI1, COL1A1, and SMA, as well as the inflammatory gene IL-6. We successfully established 3D mouse and human liver spheroid models of MASH, characterized by reduced lipid content and elevated fibrotic gene expression. IVA337 treatment not only attenuated fibrotic gene expression but also restored lipid content in the MASH spheroids, as evidenced by BODIPY staining. Immunostaining further confirmed a reduction in SMA and collagen levels following IVA337 treatment. Bulk RNA sequencing and Gene Ontology (GO) analysis revealed lipid metabolism-related genes as key effectors downstream of IVA337. Additionally, IVA337 modulated multiple signaling pathways, including IL-17, TNF, NF-kappa B, PI3K-AKT, and MAPK. Collectively, these findings demonstrate that IVA337 effectively mitigates fibrosis development in both 2D and 3D MASH models by restoring lipid homeostasis and regulating crucial fibrotic and inflammatory pathways.

2025-06-18 | GSE292999 | GEO

Metabolically and epigenetically reprogrammed splenic TRNP1hiCD8+ T cells exacerbate liver fibrosis

Project description:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.

2026-04-30 | GSE295188 | GEO