Screening the human druggable genome identifies ABHD17B as an anti-fibrotic target in hepatic stellate cells
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. Here, we perform 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 find that depletion of ABHD17B promotes the inactivation of HSCs, characterized by reduced COL1A1 and ACTA2 expression and accumulation of lipid droplets. Mice deficient in 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 >9500 genes in primary human HSCs and identify ABHD17B as a potential therapeutic target to inhibit liver fibrosis.
Authors
- David M. Wrobel
- Benjamin D. Medoff (ORCID: https://orcid.org/0000-0002-2558-0449)
- Daniela M. Santos (ORCID: https://orcid.org/0000-0002-3740-1305)
- Chan Zhou (ORCID: https://orcid.org/0000-0002-0351-6235)
- Robert P. Sparks (ORCID: https://orcid.org/0000-0002-0485-8317)
- Jörg F. Rippmann (ORCID: https://orcid.org/0000-0002-6666-6222)
- Wenyang Li (ORCID: https://orcid.org/0000-0002-1110-1099)
- Carine M. Boustany‐Kari (ORCID: https://orcid.org/0000-0003-1333-2242)
- Gary E. Aspnes
- Alan C. Mullen (ORCID: https://orcid.org/0000-0002-4096-3106)
- Zixiu Li (ORCID: https://orcid.org/0000-0002-1084-822X)
- Benjamin J. Toles
- Cheng Sun (ORCID: https://orcid.org/0000-0001-8411-4619)
- Yang Yang (ORCID: https://orcid.org/0000-0002-2383-8303)
- Sean P. Moran (ORCID: https://orcid.org/0000-0001-7672-242X)
- Julia F. Doerner
- Lorena Pantano (ORCID: https://orcid.org/0000-0002-3859-3249)
- Rory Kirchner (ORCID: https://orcid.org/0000-0003-4814-5885)
- Víctor Barrera (ORCID: https://orcid.org/0000-0003-0590-4634)
- Nahid Arghiani
- Meghan L. Brassil (ORCID: https://orcid.org/0009-0009-4235-058X)
- Peng Zhou (ORCID: https://orcid.org/0000-0001-8619-1124)
- Jennifer A. Smith (ORCID: https://orcid.org/0000-0002-8354-2272)
- Michael Schuler (ORCID: https://orcid.org/0009-0008-4933-4972)
- Arden Weilheimer
- Jennifer Y. Chen
- Shannan J. Ho Sui (ORCID: https://orcid.org/0000-0002-6191-4709)
Institutions
- Broad Institute (US)
- Boehringer Ingelheim (Germany) (DE)
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- University of California, San Francisco (US)
- Peking University (CN)
- University of Massachusetts Amherst (US)
- Massachusetts General Hospital (US)
- Boehringer Ingelheim (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-02
- DOI
- https://doi.org/10.1038/s41467-025-56900-z
- Citations
- 2
- Primary Topic
- Liver physiology and pathology
- Type
- article
- Field-Weighted Citation Impact
- 2.64
Funders
- Boehringer Ingelheim