Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease

Qinqin Ouyang, Jiaqi Su, Yixuan Li, Haiping Liao, Haiying Guo, Yanan Sun, Xiaoyu Wang, Juan Chen, Josephine Thinwa, Wen-Xing Ding, Herbert Tilg, Fazheng Ren (), Hao Zhang () and Rong Liu ()
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Qinqin Ouyang: China Agricultural University
Jiaqi Su: ETH Zurich
Yixuan Li: China Agricultural University
Haiping Liao: China Agricultural University
Haiying Guo: China Agricultural University
Yanan Sun: China Agricultural University
Xiaoyu Wang: China Agricultural University
Juan Chen: China Agricultural University
Josephine Thinwa: UT Southwestern Medical Center
Wen-Xing Ding: The University of Kansas Medical Center
Herbert Tilg: Medical University Innsbruck
Fazheng Ren: China Agricultural University
Hao Zhang: China Agricultural University
Rong Liu: China Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are two common liver disorders characterized by abnormal lipid accumulation. Our study found reduced levels of GTPase-activating protein-binding protein1 (G3BP1) in patients with MASLD and MASH, suggesting its involvement in these liver disorders. Hepatocyte-specific G3BP1 knockout (G3BP1 HKO) male mice had more severe MASLD and MASH than their corresponding controls. Intriguingly, the G3BP1 HKO MASLD model male mice exhibit dysregulated autophagy, and biochemical analyses demonstrated that G3BP1 promotes autophagosome-lysosome fusion through direct interactions with the SNARE proteins STX17 and VAMP8. We also show that hepatic knockout of G3BP1 promotes de novo lipogenesis, and ultimately found that G3BP1 is required for the nuclear translocation of the well-known liver-lipid-regulating transcription factor TFE3. Taken together, our results suggest that G3BP1 should be investigated as a potential target for developing medical interventions to treat MASLD and MASH.

Date: 2025
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DOI: 10.1038/s41467-025-63022-z

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