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<p>Indirect hepatotoxicity remains a major challenge in drug development because of limited evaluation tools and mechanistic insight. Here, we construct three-dimensional multi-lineage hepatic organoids comprising five liver cell types derived from human embryonic stem cells, and in a screen of 58 hepatotoxic drugs, identify imipramine as an inducer of indirect hepatotoxicity. Imipramine specifically engages tyrosine kinase receptor B expressed by non-parenchymal hepatic stellate cells, activating the p53/hnRNPA2B1/DGCR8 pathway, which drives selective enrichment of microRNA-34a-3p in hepatic stellate cell–derived exosomes, thereby converting them into toxic exosomes. These toxic exosomes transfer microRNA-34a-3p to hepatocytes, where it disrupts cellular homeostasis by downregulating the anti-apoptotic protein XIAP, thereby activating caspase3 and inducing apoptosis. Consistently, imipramine long-term gavage in vivo triggers hepatic stellate cell apoptosis and toxic exosome–mediated hepatocyte injury without direct hepatocyte toxicity. Our findings establish a biomimetic organoid platform for precision drug testing and highlight the central role of intercellular communication in drug-induced liver injury.</p>

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Multi-lineage hepatic organoids reveal toxic exosome mediated indirect hepatotoxicity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月19日

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  • Lei Sun,
  • Yuying Zhang,
  • Yudi Niu,
  • He Yang,
  • Lyu Zhou,
  • Xiaodong Jia,
  • Yihan Chen,
  • Zhiqiang Liu,
  • Tiantian Wang,
  • Kaini Liang,
  • Dongdong Fan,
  • Sida Ling,
  • Zhen Zeng,
  • Yanan Du

摘要

Indirect hepatotoxicity remains a major challenge in drug development because of limited evaluation tools and mechanistic insight. Here, we construct three-dimensional multi-lineage hepatic organoids comprising five liver cell types derived from human embryonic stem cells, and in a screen of 58 hepatotoxic drugs, identify imipramine as an inducer of indirect hepatotoxicity. Imipramine specifically engages tyrosine kinase receptor B expressed by non-parenchymal hepatic stellate cells, activating the p53/hnRNPA2B1/DGCR8 pathway, which drives selective enrichment of microRNA-34a-3p in hepatic stellate cell–derived exosomes, thereby converting them into toxic exosomes. These toxic exosomes transfer microRNA-34a-3p to hepatocytes, where it disrupts cellular homeostasis by downregulating the anti-apoptotic protein XIAP, thereby activating caspase3 and inducing apoptosis. Consistently, imipramine long-term gavage in vivo triggers hepatic stellate cell apoptosis and toxic exosome–mediated hepatocyte injury without direct hepatocyte toxicity. Our findings establish a biomimetic organoid platform for precision drug testing and highlight the central role of intercellular communication in drug-induced liver injury.