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

Wenyang Li, Robert P. Sparks, Cheng Sun, Yang Yang, Lorena Pantano, Rory Kirchner, Nahid Arghiani, Arden Weilheimer, Benjamin J. Toles, Jennifer Y. Chen, Sean P. Moran, Victor Barrera, Zixiu Li, Peng Zhou, Meghan L. Brassil, David Wrobel, Shannan J. Ho Sui, Gary Aspnes, Michael Schuler, Jennifer Smith, Benjamin D. Medoff, Chan Zhou, Carine M. Boustany-Kari, Jörg F. Rippmann, Daniela M. Santos, Julia F. Doerner and Alan C. Mullen ()
Additional contact information
Wenyang Li: Massachusetts General Hospital
Robert P. Sparks: Massachusetts General Hospital
Cheng Sun: Massachusetts General Hospital
Yang Yang: Harvard Medical School
Lorena Pantano: Harvard T.H. Chan School of Public Health
Rory Kirchner: Harvard T.H. Chan School of Public Health
Nahid Arghiani: University of Massachusetts Chan Medical School
Arden Weilheimer: University of Massachusetts Chan Medical School
Benjamin J. Toles: University of Massachusetts Chan Medical School
Jennifer Y. Chen: Massachusetts General Hospital
Sean P. Moran: Massachusetts General Hospital
Victor Barrera: Harvard T.H. Chan School of Public Health
Zixiu Li: University of Massachusetts Chan Medical School
Peng Zhou: University of Massachusetts Chan Medical School
Meghan L. Brassil: University of Massachusetts Amherst
David Wrobel: Harvard Medical School
Shannan J. Ho Sui: Harvard T.H. Chan School of Public Health
Gary Aspnes: Biberach a.d. Riss
Michael Schuler: Biberach a.d. Riss
Jennifer Smith: Harvard Medical School
Benjamin D. Medoff: Harvard Medical School
Chan Zhou: University of Massachusetts Chan Medical School
Carine M. Boustany-Kari: Boehringer Ingelheim Pharmaceuticals Inc.
Jörg F. Rippmann: Biberach a.d. Riss
Daniela M. Santos: Boehringer Ingelheim Pharmaceuticals Inc.
Julia F. Doerner: Biberach a.d. Riss
Alan C. Mullen: Massachusetts General Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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. 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.

Date: 2025
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DOI: 10.1038/s41467-025-56900-z

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