摘要Identification of compounds to modulate NADPH metabolism is crucial for understanding complex diseases and developing effective therapies.However,the complex nature of NADPH metabolism poses challenges in achieving this goal.In this study,we proposed a novel strategy named NADPHnet to predict key proteins and drug-target interactions related to NADPH metabolism via network-based methods.Different from traditional approaches only focusing on one single protein,NADPHnet could screen compounds to modulate NADPH metabolism from a comprehensive view.Specifically,NADPHnet identified key proteins involved in regulation of NADPH metabolism using network-based methods,and characterized the impact of natural products on NADPH metabolism using a combined score,NADPH-Score.NADPHnet demonstrated a broader applicability domain and improved accuracy in the external validation set.This approach was further employed along with molecular docking to identify 27 compounds from a natural product library,6 of which exhibited concentration-dependent changes of cellular NADPH level within 100μM,with Oxyberberine showing promising effects even at 10 μM.Mechanistic and pathological analyses of Oxyberberine suggest potential novel mechanisms to affect diabetes and cancer.Overall,NADPHnet offers a promising method for prediction of NADPH metabolism modulation and advances drug discovery for complex diseases.