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

Zhang C, Chao X, Williams SN, Wei X, DiGirolamo AM, Bajracharya A, Ma L, Huang M, Dunn N, Liu W, Ueda K, …, Ding WX · 2026 · The Journal of clinical investigation · Atlas ID ZHANG2026

What this study shows

TSC1 loss drives non-canonical mTORC1-mediated TFEB nuclear translocation, promoting hepatocyte-to-biliary plasticity and spontaneous aggressive HCC in mice; Tsc1/Tfeb double knockout rescues the phenotype.

Abstract

ShowHide

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. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation.

Read the full abstract on PubMed →

At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mouse + Human (HCC)); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Mouse + Human (HCC)
Journal	The Journal of clinical investigation
Year	2026
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1172/JCI206334 · PMID 42560776

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Tsc1 knockout (mTORC1 hyperactivation)
Target	mTORC1-TFEB
Model	Mouse + Human
Effect	Promotes hepatocyte plasticity and high-grade HCC malignancy

In the Atlas

Links in the pathway map

Supports TSC1/TSC2 inhibits mTORC1
Points the other way on mTORC1 inhibits TFEB

Cite this paper

ShowHide

Zhang, C., Chao, X., Williams, S. N., Wei, X., DiGirolamo, A. M., Bajracharya, A., Ma, L., Huang, M., Dunn, N., Liu, W., Ueda, K., Sugimoto, M., Ballabio, A., Ni, H. M., & Ding, W. X. (2026). Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma. The Journal of clinical investigation. https://doi.org/10.1172/JCI206334

@article{ZHANG2026,
  author       = {Zhang, C. and Chao, X. and Williams, S. N. and Wei, X. and DiGirolamo, A. M. and Bajracharya, A. and Ma, L. and Huang, M. and Dunn, N. and Liu, W. and Ueda, K. and Sugimoto, M. and Ballabio, A. and Ni, H. M. and Ding, W. X.},
  title        = {{Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma}},
  journal      = {The Journal of clinical investigation},
  year         = {2026},
  doi          = {10.1172/JCI206334},
  note         = {PMID: 42560776},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record ZHANG2026) [Data set]. https://mtor-atlas.org/study/ZHANG2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_ZHANG2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record ZHANG2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/ZHANG2026/},
  doi          = {10.5281/zenodo.22059963}
}

Was this page useful?