Faculty, Staff and Student Publications

Publication Date

1-9-2025

Journal

Nature Communications

Abstract

Liver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. Analysis of human data confirms a strong correlation between HSC ATF4 expression and liver fibrosis progression. Importantly, a small molecule inhibitor targeting ATF4 translation effectively mitigates liver fibrosis. Together, our findings identify a mechanism promoting liver fibrosis and reveal new opportunities for treating this otherwise non-targetable disease.

Keywords

Hepatic Stellate Cells, Activating Transcription Factor 4, Animals, Liver Cirrhosis, Humans, Epithelial-Mesenchymal Transition, Mice, Transforming Growth Factor beta, Mice, Inbred C57BL, Endoplasmic Reticulum Stress, Male, Epigenesis, Genetic, Mechanisms of disease, Molecular medicine, Epithelial-mesenchymal transition

DOI

10.1038/s41467-024-55738-1

PMID

39789010

PMCID

PMC11718104

PubMedCentral® Posted Date

1-9-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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