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PreprintCited by 5Liver physiology and pathologyLiver Disease Diagnosis and TreatmentDrug-Induced Hepatotoxicity and Protection

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Screening the human druggable genome identifies ABHD17B as an anti-fibrotic target in hepatic stellate cells

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Li, Wenyang, Sparks, Robert P., Sun, Cheng, Yang, Yang, Pantano, Lorena, Kirchner, Rory, Weilheimer, Arden, Toles, Benjamin J., Chen, Jennifer Y., Moran, Sean P., Barrera, Victor, Li, Zixiu, Zhou, Peng, Brassil, Meghan L., Wrobel, David, Sui, Shannan J. Ho, Aspnes, Gary, Schuler, Michael, Smith, Jennifer, Medoff, Benjamin D., Zhou, Chan, Boustany-Kari, Carine M., Rippmann, Jörg F., Santos, Daniela M., Doerner, Julia F., Mullen, Alan C.·2023·Nature Communications
DOI 10.1101/2023.08.07.551744PMC PMC11873113

Preprint — published as 10.1038/s41467-025-56900-z · Paper page

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Abstract

Hepatic stellate cells (HSCs) are activated with chronic liver injury and transdifferentiate into myofibroblasts, which produce excessive extracellular matrices that form the fibrotic scar. While the progression of fibrosis is understood to be the cause of end-stage liver disease, there are no approved therapies directed at interfering with the activity of HSC myofibroblasts. We performed a high-throughput small interfering RNA (siRNA) screen in primary human HSC myofibroblasts to identify gene products necessary for the fibrotic phenotype of HSCs. We found that depletion of ABHD17B promotes the inactivation of HSCs, characterized by reduced COL1A1 and ACTA2 expression and accumulation of lipid droplets. Mice deficient for Abhd17b are also protected from fibrosis in the setting of in vivo liver injury. While ABHD17B is a depalmitoylase, our data suggest that ABHD17B promotes fibrosis through pathways independent of depalmitoylation that include interaction with MYO1B to modulate gene expression and HSC migration. Together, our results provide an analysis of the phenotypic consequences for siRNAs targeting RNAs from >9,500 genes in primary human HSCs and identify ABHD17B as a potential therapeutic target to inhibit liver fibrosis.

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Metadata

Authors
Li, W., Sparks, R. P., Sun, C., Yang, Y., Pantano, L., Kirchner, R., Weilheimer, A., Toles, B. J., Chen, J. Y., Moran, S. P., Barrera, V., Li, Z., Zhou, P., Brassil, M. L., Wrobel, D., Sui, S. J. H., Aspnes, G., Schuler, M., Smith, J., Medoff, B. D., Zhou, C., Boustany-Kari, C. M., Rippmann, J. F., Santos, D. M., Doerner, J. F., & Mullen, A. C.
Affiliations
  • Harvard University (US)
  • University of Massachusetts Chan Medical School (US)
  • Boehringer Ingelheim (Germany) (DE)
  • Broad Institute (US)
Corresponding author
Mullen, Alan C.
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2023-08-07
Volume
16
Issue
1
Pages
2109-2109
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2023.08.07.551744
PMC
PMC11873113
OpenAlex
W4408080607
Cited by
5
References
1
Citations by year
2026: 3 · 2025: 2
FWCI
2.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Boehringer Ingelheim
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
hepatic stellate cells, liver fibrosis, myofibroblast transdifferentiation, depalmitoylation, MYO1B, lipid droplets, COL1A1, ACTA2, HSC migration, siRNA screen
MeSH terms
Collagen Type I, alpha 1 Chain, Actins, Animals, Cell Movement, Humans, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Mice, Knockout, Collagen Type I, RNA, Small Interfering, Mice, Hepatic Stellate Cells, Myofibroblasts, Lipid Droplets

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