Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease and lacks guaranteed pharmacological therapeutic options. In this study, we applied a network-based framework for comprehensively identifying candidate flavonoids for the prevention and/or treatment of NAFLD. Flavonoid-target interaction information was obtained from combining experimentally validated data and results obtained using a recently developed machine-learning model, AI-DTI. Flavonoids were then prioritized by calculating the network proximity between flavonoid targets and NAFLD-associated proteins. The preventive effects of the candidate flavonoids were evaluated using FFA-induced hepatic steatosis in HepG2 and AML12 cells. We reconstructed the flavonoid-target network and found that the number of re-covered compound-target interactions was significantly higher than the chance level. Proximity scores have successfully rediscovered flavonoids and their potential mechanisms that are reported to have therapeutic effects on NAFLD. Finally, we revealed that discovered candidates, particularly glycitin, significantly attenuated lipid accumulation and moderately inhibited intracellular reactive oxygen species production. We further confirmed the affinity of glycitin with the predicted target using molecular docking and found that glycitin targets are closely related to several proteins involved in lipid metabolism, inflammatory responses, and oxidative stress. The predicted network-level effects were validated at the levels of mRNA. In summary, our study offers and validates network-based methods for the identification of candidate flavonoids for NAFLD.