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; Alan C Mullen

doi:10.1038/s41467-025-56900-z

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

Nat Commun. 2025 Mar 2;16(1):2109. doi: 10.1038/s41467-025-56900-z.

Authors

Wenyang Li^#^{1

2

3}, Robert P Sparks^#^{1

2}, Cheng Sun^#^{1

2}, Yang Yang^{2

4}, Lorena Pantano⁵, Rory Kirchner⁵, Nahid Arghiani⁶, Arden Weilheimer⁶, Benjamin J Toles⁶, Jennifer Y Chen^{1

2

7

8}, Sean P Moran^{1

2}, Victor Barrera⁵, Zixiu Li⁹, Peng Zhou⁹, Meghan L Brassil^{10

11}, David Wrobel¹², Shannan J Ho Sui⁵, Gary Aspnes¹³, Michael Schuler¹³, Jennifer Smith¹², Benjamin D Medoff^{2

4}, Chan Zhou⁹, Carine M Boustany-Kari¹⁴, Jörg F Rippmann¹³, Daniela M Santos¹⁴, Julia F Doerner¹³, Alan C Mullen^{15

16

17}

Affiliations

¹ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
⁴ Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵ Harvard Chan Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁷ Department of Medicine, University of California, San Francisco, CA, USA.
⁸ Liver Center, Department of Medicine, University of California, San Francisco, CA, USA.
⁹ Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹⁰ Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, USA.
¹¹ UMass Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹² ICCB-Longwood Screening Facility, Harvard Medical School, Boston, MA, USA.
¹³ Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a.d. Riss, Biberach, Germany.
¹⁴ Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.
¹⁵ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. alan.mullen@umassmed.edu.
¹⁶ Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA, USA. alan.mullen@umassmed.edu.
¹⁷ Broad Institute, Cambridge, MA, USA. alan.mullen@umassmed.edu.

^# Contributed equally.

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.

MeSH terms

Actins / genetics
Actins / metabolism
Animals
Cell Movement / genetics
Collagen Type I / genetics
Collagen Type I / metabolism
Collagen Type I, alpha 1 Chain
Hepatic Stellate Cells* / drug effects
Hepatic Stellate Cells* / metabolism
Hepatic Stellate Cells* / pathology
Humans
Lipid Droplets / metabolism
Liver / metabolism
Liver / pathology
Liver Cirrhosis* / genetics
Liver Cirrhosis* / metabolism
Liver Cirrhosis* / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myofibroblasts / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism

Substances

RNA, Small Interfering
Collagen Type I
Actins
Collagen Type I, alpha 1 Chain
ACTA2 protein, human