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
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons