AUTHOR=Gao Jian , Yin Zuojing , Wu Zhuanbin , Sheng Zhen , Ma Chao , Chen Rui , Zhang Xiongwen , Tang Kailin , Fei Jian , Cao Zhiwei TITLE=Probing Synergistic Targets by Natural Compounds for Hepatocellular Carcinoma JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=Volume 9 - 2021 YEAR=2021 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.715762 DOI=10.3389/fcell.2021.715762 ISSN=2296-634X ABSTRACT=Background: Designing combination drugs for malignant cancers has been restricted due to scarcity of synergy-medicated targets, while some natural compounds have demonstrated with potential to enhance anti-cancer effects. Methods: We here explored the feasibility of probing synergy-mediated targets by Berberine (BER) and Evodiamine (EVO) in hepatocellular carcinoma (HCC). Using the genomics-derived HCC signaling networks of compound treatment, NF-κB and c-JUN were inferred as key responding elements with transcriptional activity co-inhibited during the synergistic cytotoxicity induction in BEL-7402 cells. Then, selective co-inhibitors of NF-κB and c-JUN were tested demonstrating similar synergistic anti-proliferation activity. Results: Consistent with in vivo of zebrafish, co-inhibitors were found to significantly reduce tumor growth by 79% and metastasis by 96% compared to blank control, accompanied by anti-angiogenic activity. In analysis of 365 HCC individuals, both-low expression group showed significantly lower malignancies and better prognosis, with the median survival time increased from 67% to 213%, comparing to the rest groups. Conclusions: Together, NF-κB and c-JUN were identified as promising synergistic inducers in developing anti-HCC therapies. Also, our method may provide a feasible strategy to explore new targeting space from natural compounds, opening opportunities for the rational design of combinational formulations in combatting malign cancers.