Identification of gene-phenotype connectivity associated with flavanone naringenin by functional network analysis

Naringenin, extracted from grapefruits and citrus fruits, is a bioactive flavonoid with antioxidative, anti-inflammatory, antifibrogenic, and anticancer properties. In the past two decades, the growth of publications of naringenin in PubMed suggests that naringenin is quickly gaining interest. However, systematically regarding its biological functions connected to its direct and indirect target proteins remains difficult but necessary. Herein, we employed a set of bioinformatic platforms to integrate and dissect available published data of naringenin. Analysis based on DrugBank and the Search Tool for the Retrieval of Interacting Genes/Proteins revealed seven direct protein targets and 102 indirect protein targets. The protein-protein interaction (PPI) network of total 109 naringenin-mediated proteins was next visualized using Cytoscape. What's more, all naringenin-mediated proteins were subject to Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis by the Database for Annotation, Visualization and Integrated Discovery, which resulted in three ESR1-related signaling pathways and prostate cancer pathway. Refined analysis of PPI network and KEGG pathway identified four genes (ESR1, PIK3CA, AKT1, and MAPK1). Further genomic analysis of four genes using cBioPortal indicated that naringenin might exert biological effects via ESR1 signaling axis. In general, this work scrutinized naringenin-relevant knowledge and provided an insight into the regulation and mediation of naringenin on prostate cancer.