DataVXAdvanced SciencePaper
journal article·2026-07Open access

Hepatoma‐Derived Growth Factor Coordinates STAT3 Pathway and Exosome‐Mediated Intrahepatic Crosstalk to Control Hepatic Steatosis and MASLD

Jian Wen, Dong Ding, Zengpeng Zheng, Xufeng Chen, Wenjing Li, Jiaxin Shen, Zhiwei Huang, Peng Tan, Junjie Bai, Xia Fang, Baofang Xing, Puyuan Hu, Linghao Xu, Haokai Yu, Yixi Wang, Zongzhe Jiang, Yang Long, Tiejun Zhou, Mingxin Ye, Yu Jiang, Aoyuan Cui, Hong Li, Qiurong Ding, Yong Xu, Yu Li, Weitong Su, Feng Shen, Chenlin Gao, Wenguang Fu

Advanced Science· Volume 13· Issue 42
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Abstract

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease has become a predominant cause of chronic liver disease worldwide and represents a major clinical management challenge owing to the scarcity of effective therapeutic interventions. However, the molecular mechanisms driving MASLD progression remain incompletely understood. Here, we identify hepatoma‐derived growth factor (HDGF) as a key regulator that integrates lipogenesis with intrahepatic inflammation in MASLD pathogenesis. Hepatic HDGF deficiency profoundly protects mice from high‐fat, high‐sucrose diet‐induced hepatic steatosis and inflammation. Mechanistically, HDGF promotes lipogenesis and hepatic steatosis by facilitating S6K1‐dependent phosphorylation of STAT3 at Ser727. Consistently, pharmacological inhibition of STAT3 by S3I‐201 abolishes HDGF‐induced lipogenic gene expression and hepatic steatosis in mouse models. Importantly, phosphorylation of HDGF at Ser165 is essential for its exosomal secretion from hepatocytes, thereby triggering proinflammatory macrophage activation. In humans, both serum and hepatic levels of HDGF are elevated and positively correlated with MASLD progression. Together, these findings uncover a mechanism that couples hepatic lipogenesis to intrahepatic macrophage activation, driving both steatosis and inflammation in MASLD. Targeting the HDGF‐STAT3 pathway and exosomal HDGF secretion may represent a potential therapeutic strategy for ameliorating metabolic dysfunction and hepatic inflammation in MASLD and related disorders.
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Research context

OpenAlex topics: Liver Disease Diagnosis and Treatment · Liver Disease and Transplantation · Fibroblast Growth Factor Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of General Surgery (Hepatobiliary Surgery) Biliary‐Pancreatic Center The Affiliated Hospital Southwest Medical University Luzhou Sichuan China

Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City Academician (Expert) Workstation of Sichuan Province The Affiliated Hospital Southwest Medical University Luzhou Sichuan China

Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai China

Department of Endocrinology and Metabolism Metabolic Vascular Disease Key Laboratory of Sichuan Province The Affiliated Hospital of Southwest Medical University Luzhou Sichuan China

State Key Laboratory of Food Nutrition and Safety College of Biotechnology Tianjin University of Science and Technology Tianjin China

Experimental Medicine Center Department of Endocrinology and Metabolism Metabolic Vascular Disease Key Laboratory of Sichuan Province The Affiliated Hospital of Southwest Medical University Luzhou Sichuan China

Department of Pathology The Affiliated Hospital Southwest Medical University Luzhou Sichuan China

Department of Gastroenterology & Endoscopy Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China

Funding

National Natural Science Foundation of China · Shanghai Rising-Star Program · Natural Science Foundation of Shanghai Municipality

References (39)

Show source-provided references
1. 10.1016/j.jhep.2023.06.00310.1016/j.jhep.2023.06.003 ↗
2. 10.1038/nrgastro.2017.10910.1038/nrgastro.2017.109 ↗
3. 10.1016/S2468‐1253(22)00317‐X10.1016/S2468‐1253(22)00317‐X ↗
4. 10.1038/s41575‐021‐00448‐y10.1038/s41575‐021‐00448‐y ↗
5. 10.1136/gutjnl‐2023‐33059510.1136/gutjnl‐2023‐330595 ↗
6. 10.1016/S0092‐8674(00)80213‐510.1016/S0092‐8674(00)80213‐5 ↗
7. 10.1038/nrm407410.1038/nrm4074 ↗
8. 10.1016/j.molcel.2010.06.02210.1016/j.molcel.2010.06.022 ↗
9. 10.1002/hep.2984910.1002/hep.29849 ↗
10. 10.1016/j.jhep.2012.01.02910.1016/j.jhep.2012.01.029 ↗
11. 10.1038/s41568‐022‐00537‐310.1038/s41568‐022‐00537‐3 ↗
12. 10.1038/s41575‐018‐0082‐x10.1038/s41575‐018‐0082‐x ↗
13. 10.1016/j.jhep.2022.06.01210.1016/j.jhep.2022.06.012 ↗
14. 10.1038/s41568‐024‐00743‐110.1038/s41568‐024‐00743‐1 ↗
15. 10.1210/er.2019‐0003410.1210/er.2019‐00034 ↗
16. 10.1016/j.pharmthera.2023.10835210.1016/j.pharmthera.2023.108352 ↗
17. 10.1126/sciadv.ado931110.1126/sciadv.ado9311 ↗
18. 10.1038/s41467‐024‐52379‐210.1038/s41467‐024‐52379‐2 ↗
19. 10.1016/j.jhep.2025.02.00310.1016/j.jhep.2025.02.003 ↗
20. 10.1097/HEP.000000000000004210.1097/HEP.0000000000000042 ↗
21. 10.1002/hep.2470110.1002/hep.24701 ↗
22. 10.1097/HEP.000000000000145810.1097/HEP.0000000000001458 ↗
23. 10.1136/gutjnl‐2013‐30637310.1136/gutjnl‐2013‐306373 ↗
24. 10.1016/j.ejcb.2021.15116910.1016/j.ejcb.2021.151169 ↗
25. 10.1016/j.bbrc.2022.10.03210.1016/j.bbrc.2022.10.032 ↗
26. 10.1074/mcp.M115.05572310.1074/mcp.M115.055723 ↗
27. 10.1159/00048974410.1159/000489744 ↗
28. 10.1007/s10495‐015‐1200‐710.1007/s10495‐015‐1200‐7 ↗
29. 10.1126/science.107154510.1126/science.1071545 ↗
30. 10.1038/nrm302510.1038/nrm3025 ↗
31. 10.1038/s41580‐019‐0199‐y10.1038/s41580‐019‐0199‐y ↗
32. 10.1038/s41587‐021‐01156‐310.1038/s41587‐021‐01156‐3 ↗
33. 10.1515/bc.2010.14710.1515/bc.2010.147 ↗
34. 10.1038/cddis.2014.39310.1038/cddis.2014.393 ↗
35. 10.1038/s41467‐020‐17669‐510.1038/s41467‐020‐17669‐5 ↗
36. 10.1002/hep.3091910.1002/hep.30919 ↗
37. 10.1016/j.jhep.2009.10.00210.1016/j.jhep.2009.10.002 ↗
38. 10.1164/rccm.201512‐2498OC10.1164/rccm.201512‐2498OC ↗
39. 10.1136/gutjnl‐2019‐31963910.1136/gutjnl‐2019‐319639 ↗