AUTHOR=Liu Juan , Li Tingting , Li Ruihong , Wang Jie , Li Pengyan , Niu Ming , Zhang Le , Li Chunyu , Wang Tao , Xiao Xiaohe , Wang Jia-bo , Wang Yunfang TITLE=Hepatic Organoid-Based High-Content Imaging Boosts Evaluation of Stereoisomerism-Dependent Hepatotoxicity of Stilbenes in Herbal Medicines JOURNAL=Frontiers in Pharmacology VOLUME=Volume 13 - 2022 YEAR=2022 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.862830 DOI=10.3389/fphar.2022.862830 ISSN=1663-9812 ABSTRACT=The complexity of chemical components of herbal medicines often causes great barriers to toxicity researches. In our previous study, we have found the critical divergent hepatotoxic potential of a pair of stilbene isomers in a famous traditional Chinese herb, Polygonum multiflorum (Heshouwu in Chinese). However, the high throughput in vitro evaluation for such stereoisomerism-dependent hepatotoxicity is a critically challenge. In this study, we used a hepatic organoids-based in vitro hepatotoxic evaluation system combined with using high content imaging to differentiate in vivo organ hepatotoxicity of the 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer (cis-SG). By using such organoids platform, we successfully differentiated the two stereoisomers’ hepatotoxic potentials, which were accordance with their differences in rodents and humans. The lesion mechanism of the toxic isomer (cis-SG) was further found as the mitochondrial injury by high content imaging; and its hepatotoxicity could be dose-depended inhibited by the mitochondrial protective agent. These results demonstrated the utility of organoids-based high content imaging approach in evaluating and predicting organ toxicity of natural products by a low cost and high throughput way. It also suggested the rationale to use long-term cultured organoids as alternative toxicology platform to early and cautiously identify hepatotoxic new drug candidates in preclinical phase.