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A novel pharmacological inhibitor of MAP4K4 activity protect against preclinical model of metabolic dysfunction-associated steatohepatitis

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by accumulation of fats in liver, chronic inflammation, hepatocytic ballooning, and fibrosis. In this study, glucosyl pyrrolo-pyrimidinone (GPPD), a newly synthesized pharmacological inhibitor of mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4) was utilized to investigate significance of MAP4K4 signaling in MASH. To elucidate the effect of GPPD, wild-type (WT,C57BL6) mice were subjected to control diet (CD), high-fat high-fructose high-cholesterol diet (MASH diet, MD), and fed with MASH diet and treated with GPPD thrice a week for 30-week period. MAP4K4 immunoblotting and activity assay showed downregulation of MAP4K4 kinase activity without altering its expression. GPPD was able to mitigate hallmarks of MASH including steatosis, inflammation, fibrosis, and liver injury. Single-nuclei RNA sequencing revealed significant downregulation of calcium/calmodulin-dependent protein kinase II (CamKII). Subsequent immunoblotting confirmed that GPPD decreased expression and phosphorylation of CamKII in hepatocytes potentially conferring protection against steatohepatitis.

ORGANISM(S): Mus musculus

PROVIDER: GSE308258 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:Metabolic Dysfunction Associated Steatohepatitis (MASH) is characterized by excess circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to the liver sinusoidal endothelial cells (LSEC) and transendothelial migration (TEM) are crucial in the inflammatory process. LSEC under lipotoxic stress develops a pro-inflammatory phenotype known as endotheliopathy. However, the mediators of endotheliopathy remain obscure. Primary mouse LSEC isolated from C57BL/6J mice on chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH, due to a choline-deficient high-fat diet (CDHFD) or FFC diet, were treated with two structurally distinct GSK3 inhibitors [LY2090314, elraglusib (9-ING-41)]. Integrated pathway analysis of mouse LSEC proteome and transcriptome indicates that leukocyte TEM and focal adhesion are major pathways altered in MASH. Kinome profiling of the LSEC phospho-proteome identified GSK3β as the major kinase hub in MASH. GSK3β activating phosphorylation was increased in primary human LSEC treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependant mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC and CDHFD-fed mice, respectively. Immunophenotyping of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib using cytometry by the time of flight showed reduced proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells infiltration.GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and may serve as a potential therapeutic strategy in human MASH.

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A novel pharmacological inhibitor of MAP4K4 activity protect against preclinical model of metabolic dysfunction-associated steatohepatitis

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