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ResearchIn-Press PreviewCell biologyHepatologyOncology Open Access | 10.1172/JCI206334

Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma

Chen Zhang,1 Xiaojuan Chao,1 Sha Neisha Williams,1 Xiaoli Wei,1 Anthony DiGirolamo,1 Alisha Bajracharya,1 Lichun Ma,2 Ming Huang,1 Nicholas Dunn,1 Wanqing Liu,3 Kaito Ueda,4 Masayuki Sugimoto,4 Andrea Ballabio,5 Hong-Min Ni,6 and Wen-Xing Ding1

1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

Find articles by Ma, L. in: PubMed | Google Scholar |

1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

Find articles by Liu, W. in: PubMed | Google Scholar

1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

Find articles by Ni, H. in: PubMed | Google Scholar

1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States of America

2Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, United States of America

3Department of Pharmaceutical Sciences, Wayne State University, Detroit, United States of America

4Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan

5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

6Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, United States of America

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Published August 6, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI206334.
Copyright © 2026, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 6, 2026 - Version history
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Abstract

Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring Tuberous Sclerosis Complex 1 (TSC1) mutations exhibits more aggressive behavior. TFEB is a master regulator of lysosomal biogenesis and cell fate. We analyzed human normal and HCC tissue arrays for TFEB and CK19 expression, as well as bulk and single-cell RNA-seq datasets from mouse and human HCC, to define TFEB-associated transcriptional programs. We performed biochemical, histological, metabolomic, and transcriptomic analyses in liver-specific Tsc1 knockout (L-Tsc1 KO) and L-Tsc1,Tfeb double KO (DKO) mice. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. L-Tsc1 KO mice showed increased hepatocyte plasticity, decreased HFN4α, increased YAP1 activation, and spontaneous HCC with increased SOX9 and CK19-positive biliary epithelial cell (BEC)-like cells at 8-12 months. Deletion of Tfeb dampened hepatic metabolic reprogramming and hepatocyte fate changes and inhibited tumor progression in L-Tsc1 KO mice. Increased TFEB activity was associated with increased YAP and SOX9 gene expression and high-grade malignant HCC in humans. These findings indicate that loss of hepatic TSC1 leads to non-canonical TFEB activation, promoting hepatocyte plasticity and tumor heterogeneity associated with high-grade malignancy in both mouse and human HCC.  

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