Endothelial Cell Glycogen Synthase Kinase 3β Promotes Lipotoxic Endotheliopathy and Liver Inflammation in MASH

Akitoshi Sano; Qianqian Guo; Khaled Warasnhe; Chady Meroueh; Nantawat Satthawiwat; Asma Hamdi; Ghefar Hmaydoosh; Xin Dai; Usman Yaqoob; Kevin D. Pavelko; Charlene Miciano; Tatiana Kisseleva; Zeba Firdaus; Patrick P. Starlinger; David Pereyra; Enis Kostallari; Petra Hirsova; Davide Povero; Samar H. Ibrahim

doi:10.1172/jci.insight.202552

Endothelial Cell Glycogen Synthase Kinase 3β Promotes Lipotoxic Endotheliopathy and Liver Inflammation in MASH

Akitoshi Sano,¹ Qianqian Guo,¹ Khaled Warasnhe,¹ Chady Meroueh,² Nantawat Satthawiwat,¹ Asma Hamdi,³ Ghefar Hmaydoosh,¹ Xin Dai,¹ Usman Yaqoob,¹ Kevin D. Pavelko,⁴ Charlene Miciano,⁵ Tatiana Kisseleva,⁶ Zeba Firdaus,⁷ Patrick P. Starlinger,⁸ David Pereyra,⁸ Enis Kostallari,¹ Petra Hirsova,¹ Davide Povero,¹ and Samar H. Ibrahim¹

Published May 5, 2026 - More info

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Abstract

In metabolic dysfunction-associated steatohepatitis (MASH), liver sinusoidal endothelial cells (LSECs) acquire a proinflammatory phenotype termed lipotoxic endotheliopathy. We previously identified glycogen synthase kinase 3β (GSK3β) as a central signaling hub in LSECs during MASH. To elucidate the molecular mechanisms and functional outcome of lipotoxicity-induced GSK3β activation in LSECs, we utilized endothelial cell-specific Gsk3β knockout (Gsk3β^△End) mice fed MASH-inducing diets. Endothelial Gsk3β deletion significantly reduced markers of lipotoxic endotheliopathy, including adhesion molecules and chemokines, alongside liver injury, inflammation, and fibrosis. Immune profiling via flow cytometry and mass cytometry by time of flight (CyTOF) identified decreased hepatic infiltration of proinflammatory myeloid populations, particularly mature dendritic cells (DCs) in Gsk3β^△End mice. In a co-culture system, GSK3β in lipotoxic LSECs promoted DCs maturation. Mechanistically, GSK3 inhibition restored lipotoxicity-induced alterations in LSEC mitochondrial morphology and respiration by regulating AMP-activated protein kinase and dynamin-related protein 1. This rescue suppressed chemokines and adhesion molecules expression, thereby limiting immune cell recruitment. Collectively, under lipotoxic stress, GSK3β amplifies mitochondrial dysfunction and inflammatory signaling in LSECs, enhancing myeloid cell homing and DC maturation. Targeting LSEC GSK3β may therefore represent a promising therapeutic strategy to mitigate LSEC driven fibro inflammatory response in human MASH.

Endothelial Cell Glycogen Synthase Kinase 3β Promotes Lipotoxic Endotheliopathy and Liver Inflammation in MASH

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Endothelial Cell Glycogen Synthase Kinase 3β Promotes Lipotoxic Endotheliopathy and Liver Inflammation in MASH

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