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Screening Potential Drugs for the Development of NAFLD Based on Drug Perturbation Gene Set
Zhengzheng Gao1, Lina Dai1, Haifeng Zhang1
1Basic Medical College of Inner Mongolia Medical University, Hohhot, China.
Abstract:
Nonalcoholic fatty liver disease (NAFLD) has become one of the problems affecting the health of the population worldwide. The progressive disease includes nonalcoholic steatohepatitis (NASH) and fibrosis, which with no approved therapy, system identification of effective drugs remains challenging. In this work, we applicated drug perturbation gene set enrichment analysis to screen drugs for the development of NAFLD. A total 15490 small-molecule compounds were analyzed in our study; based on the p value of enrichment score, 7 small-molecule compounds were found to have a potential role in NASH and fibrosis. After pathway analyses, we found indoximod had effects on nonalcoholic fatty liver disease through regulated TNFa, AP-1, AKT, PI3K, etc. Furthermore, we established the NAFLD cell model with LO2 cells induced using PA; ELISA showed that the levels of TG, ALT, and AST were significantly improved by indoximod. In summary, our study offers optimal therapeutic drugs, which may provide novel insight into the precise treatment of NAFLD and promote researches.
Insights
This study screened 15,490 compounds to identify potential treatments for nonalcoholic fatty liver disease (NAFLD). Indoximod showed promise in improving NAFLD markers in cell models, offering new therapeutic insights.
Area of Science:
- Hepatology and Pharmacology
- Drug Discovery and Development
Background:
- Nonalcoholic fatty liver disease (NAFLD) is a global health concern.
- Progressive forms like nonalcoholic steatohepatitis (NASH) and fibrosis lack approved therapies, necessitating new drug discovery.
- Identifying effective treatments for NAFLD remains a significant challenge.
Purpose of the Study:
- To screen small-molecule compounds for potential therapeutic effects on NAFLD, NASH, and fibrosis.
- To identify specific drugs that can modulate key pathways involved in NAFLD pathogenesis.
- To validate the efficacy of a candidate drug in a cellular model of NAFLD.
Main Methods:
- Drug perturbation gene set enrichment analysis was applied to screen 15,490 small-molecule compounds.
- Pathway analysis was conducted to understand the mechanism of action of identified compounds.
- A cellular NAFLD model using LO2 cells induced with PA was established for validation.
- ELISA was used to quantify key biomarkers like TG, ALT, and AST.
Main Results:
- Seven small-molecule compounds were identified as potentially effective against NASH and fibrosis based on enrichment scores.
- Indoximod was identified as a promising candidate, showing effects on NAFLD through regulation of TNFa, AP-1, AKT, and PI3K pathways.
- Indoximod significantly improved TG, ALT, and AST levels in the established NAFLD cell model.
Conclusions:
- This study identified indoximod as a potential therapeutic agent for nonalcoholic fatty liver disease.
- The findings provide novel insights into precise NAFLD treatment strategies.
- Further research into indoximod may promote the development of effective therapies for NAFLD, NASH, and fibrosis.
