Dissect new mechanistic insights for geniposide efficacy on the hepatoprotection using multiomics approach.

A multi-omics approach could yield in-depth mechanistic insights. Here, we performed an integrated analysis of miRNAome, proteome and metabolome, aimed to investigate the underlying mechanism of active product geniposide in ethanol-induced apoptosis. We found that integrative meta-analysis identified 28 miRNAs, 20 proteins and 7 metabolites significantly differentially expressed, respectively. Further analysis identified geniposide extensively regulated multiple metabolism pathways and the most important related pathway was citrate cycle (TCA cycle). In addition, geniposide can improve energy metabolism benefits using the Extracellular Flux Analyzer. Of particular significance, miR-144-5p exhibits a high positive correlation with oxoglutaric acid, isocitrate dehydrogenase (IDH) 1 and 2 that involved in the TCA cycle. Furthermore,we discovered that miR-144-5p regulates TCA cycle metabolism through IDH1 and IDH2. Collectively, we describe for the first time the hepatoprotective effect of geniposide decreased miR-144-5p level, capable of regulating TCA cycle by directly targeting IDH1 and IDH2 and promoting functional consequences in cells. Integrating metabolomics, miRNAomics and proteomics approach and thereby analyzing microRNAs and proteins as well as metabolites can give valuable information about the functional regulation pattern and action mechanism of natural products.