Peer-reviewedCC BYEMBO Reports
VGLL4 enhances PDK4 transcription and promotes metabolic dysfunction-associated fatty liver disease
8 affiliations
- 1Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences
- 2Department of Urology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University
- 3Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences
- 4Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
- 5Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education
- 6School of Basic Medical Sciences, Dali University
- 7Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, University of Chinese Academy of Sciences
- 8Department of Emergency and Critical Care Medicine, Shanghai Pudong New Area People’s Hospital
Abstract
MAFLD is a global epidemic with a limited number of approved targeted therapies, underscoring the urgent need to define its underlying regulatory mechanisms. Here, we identify VGLL4 as a positive regulator of MAFLD progression. Hepatocyte-specific overexpression of Vgll4 induces hepatic steatosis, insulin resistance, and inflammation, whereas its knockout protects mice from HFD-induced metabolic dysfunction. Mechanistically, VGLL4 strengthens the interaction between TEAD4 and CEBPA and promotes the cooperative activation of Pdk4 expression. Functional studies identify PDK4 as a downstream effector, as its knockdown alleviates VGLL4-exacerbated hepatosteatosis in vivo. YAP attenuates this regulatory mechanism and suppresses Pdk4 transcription during hepatic steatosis. Notably, administration of Super-TDU, a peptide that disrupts the VGLL4–TEADs interaction, significantly alleviates hepatic steatosis in both HFD-fed mice and Vgll4-overexpressing mice. Our findings unveil the VGLL4–TEAD4/CEBPA–PDK4 axis as a key driver of MAFLD and demonstrate that its pharmacological blockade alleviates hepatic steatosis in model mice.
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BibTeX
@article{chen2026vgll4,
title = {{VGLL4 enhances PDK4 transcription and promotes metabolic dysfunction-associated fatty liver disease}},
author = {Yixing Chen and Xiaodong Wang and Wentao Yu and Meixi Gong and Yi Lu and Jinjin Xu and Hao Zhang and Ruizeng Yang and Haoen Zhang and Haoran Gao and Zhuoqun Gao and Jiayan Yan and Zhifeng Jiang and Shiyu Zhang and Xueyan Ma and Jing Yu and Fang Wei and Qiang Fu and Yi Zhou and Jian Zhou and Jian Wan and Yunyun Jin and Lei Zhang},
journal = {EMBO Reports},
year = {2026},
month = sep,
doi = {10.1038/s44319-026-00934-x},
url = {https://doi.org/10.1038/s44319-026-00934-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - VGLL4 enhances PDK4 transcription and promotes metabolic dysfunction-associated fatty liver disease
AU - Yixing Chen
AU - Xiaodong Wang
AU - Wentao Yu
AU - Meixi Gong
AU - Yi Lu
AU - Jinjin Xu
AU - Hao Zhang
AU - Ruizeng Yang
AU - Haoen Zhang
AU - Haoran Gao
AU - Zhuoqun Gao
AU - Jiayan Yan
AU - Zhifeng Jiang
AU - Shiyu Zhang
AU - Xueyan Ma
AU - Jing Yu
AU - Fang Wei
AU - Qiang Fu
AU - Yi Zhou
AU - Jian Zhou
AU - Jian Wan
AU - Yunyun Jin
AU - Lei Zhang
PY - 2026
DA - 2026/09/01
JO - EMBO Reports
DO - 10.1038/s44319-026-00934-x
UR - https://doi.org/10.1038/s44319-026-00934-x
AB - MAFLD is a global epidemic with a limited number of approved targeted therapies, underscoring the urgent need to define its underlying regulatory mechanisms. Here, we identify VGLL4 as a positive regulator of MAFLD progression. Hepatocyte-specific overexpression of Vgll4 induces hepatic steatosis, insulin resistance, and inflammation, whereas its knockout protects mice from HFD-induced metabolic dysfunction. Mechanistically, VGLL4 strengthens the interaction between TEAD4 and CEBPA and promotes the cooperative activation of Pdk4 expression. Functional studies identify PDK4 as a downstream effector, as its knockdown alleviates VGLL4-exacerbated hepatosteatosis in vivo. YAP attenuates this regulatory mechanism and suppresses Pdk4 transcription during hepatic steatosis. Notably, administration of Super-TDU, a peptide that disrupts the VGLL4–TEADs interaction, significantly alleviates hepatic steatosis in both HFD-fed mice and Vgll4-overexpressing mice. Our findings unveil the VGLL4–TEAD4/CEBPA–PDK4 axis as a key driver of MAFLD and demonstrate that its pharmacological blockade alleviates hepatic steatosis in model mice.
SN - 1469-3178
ER -