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Updated: Nov 25, 2025
Using Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells for Drug Discovery
Published on: May 19, 2018
Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the
Maddalena Parafati1,2, Sang Hyo Bae1, R Jason Kirby2
1Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Abstract:
Non-alcoholic fatty liver disease (NAFLD) has a large impact on global health. At the onset of disease, NAFLD is characterized by hepatic steatosis defined by the accumulation of triglycerides stored as lipid droplets. Developing therapeutics against NAFLD and progression to non-alcoholic steatohepatitis (NASH) remains a high priority in the medical and scientific community. Drug discovery programs to identify potential therapeutic compounds have supported high throughput/high-content screening of in vitro human-relevant models of NAFLD to accelerate development of efficacious anti-steatotic medicines. Human induced pluripotent stem cell (hiPSC) technology is a powerful platform for disease modeling and therapeutic assessment for cell-based therapy and personalized medicine. In this study, we applied AstraZeneca's chemogenomic library, hiPSC technology and multiplexed high content screening to identify compounds that significantly reduced intracellular neutral lipid content. Among 13,000 compounds screened, we identified hits that protect against hiPSC-derived hepatic endoplasmic reticulum stress-induced steatosis by a mechanism of action including inhibition of the cyclin D3-cyclin-dependent kinase 2-4 (CDK2-4)/CCAAT-enhancer-binding proteins (C/EBPα)/diacylglycerol acyltransferase 2 (DGAT2) pathway, followed by alteration of the expression of downstream genes related to NAFLD. These findings demonstrate that our phenotypic platform provides a reliable approach in drug discovery, to identify novel drugs for treatment of fatty liver disease as well as to elucidate their underlying mechanisms.
Insights
Researchers identified compounds that reduce fat buildup in liver cells, offering new hope for treating non-alcoholic fatty liver disease (NAFLD). This discovery accelerates the development of effective anti-steatotic medicines for NAFLD and non-alcoholic steatohepatitis (NASH).
Area of Science:
- Hepatology and Drug Discovery
- Stem Cell Biology and Disease Modeling
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a significant global health concern, characterized by hepatic steatosis (triglyceride accumulation).
- Developing effective therapeutics for NAFLD and its progression to non-alcoholic steatohepatitis (NASH) is a medical and scientific priority.
- Human induced pluripotent stem cell (hiPSC) technology offers a robust platform for disease modeling and therapeutic assessment.
Purpose of the Study:
- To identify novel compounds that reduce intracellular neutral lipid content in a human-relevant model of NAFLD.
- To leverage hiPSC technology and high-content screening for accelerated drug discovery of anti-steatotic medicines.
- To elucidate the mechanism of action for identified therapeutic compounds.
Main Methods:
- Screening of AstraZeneca's chemogenomic library (13,000 compounds) using hiPSC-derived hepatocytes.
- Application of multiplexed high-content screening to quantify intracellular neutral lipid accumulation.
- Investigating the molecular pathways affected by hit compounds, including the CDK2-4/C/EBPα/DGAT2 pathway.
Main Results:
- Identification of compounds that significantly reduce lipid droplet accumulation in hiPSC-derived hepatocytes.
- Demonstration that identified hits protect against endoplasmic reticulum stress-induced steatosis.
- Elucidation of a mechanism involving inhibition of the CDK2-4/C/EBPα/DGAT2 pathway and downstream gene alterations.
Conclusions:
- The developed phenotypic screening platform reliably identifies novel drug candidates for fatty liver disease.
- The study successfully identified compounds targeting key pathways implicated in NAFLD pathogenesis.
- This approach accelerates the discovery of efficacious anti-steatotic medicines and deepens understanding of NAFLD mechanisms.
