Ensartinib是一种获批的ALK抑制剂，在中国用作晚期ALK阳性非小细胞肺癌的一线治疗。然而，恩沙替尼的肝毒性严重限制了其临床应用，且其调控机制仍不清楚。在这里，通过转录组分析，我们发现TXNIP的转录激活是恩沙替尼引起的肝功能障碍的主要原因。高 TXNIP 水平和异常 TXNIP 易位通过线粒体功能障碍和肝细胞凋亡严重损害肝功能，而 TXNIP 缺乏会减弱恩沙替尼治疗下的肝细胞凋亡。 ensartinib 诱导的 TXNIP 增加与 AKT 抑制有关，并由 MondoA 介导。通过筛选潜在的TXNIP抑制剂，我们发现天然多酚类黄酮芦丁与大多数报道的TXNIP抑制剂不同，可以通过与TXNIP结合并部分促进其蛋白酶体降解来抑制TXNIP。进一步的研究表明芦丁可以减轻恩沙替尼的肝毒性而不拮抗其抗肿瘤作用。因此，我们认为 TXNIP 是恩沙替尼诱导肝毒性的关键原因，而芦丁是 TXNIP 干预的潜在临床安全可行的治疗策略。© 2024。作者。

Ensartinib, an approved ALK inhibitor, is used as a first-line therapy for advanced ALK-positive non-small cell lung cancer in China. However, the hepatotoxicity of ensartinib seriously limits its clinical application and the regulatory mechanism is still elusive. Here, through transcriptome analysis we found that transcriptional activation of TXNIP was the main cause of ensartinib-induced liver dysfunction. A high TXNIP level and abnormal TXNIP translocation severely impaired hepatic function via mitochondrial dysfunction and hepatocyte apoptosis, and TXNIP deficiency attenuated hepatocyte apoptosis under ensartinib treatment. The increase in TXNIP induced by ensartinib is related to AKT inhibition and is mediated by MondoA. Through screening potential TXNIP inhibitors, we found that the natural polyphenolic flavonoid rutin, unlike most reported TXNIP inhibitors can inhibit TXNIP by binding to TXNIP and partially promoting its proteasomal degradation. Further studies showed rutin can attenuate the hepatotoxicity of ensartinib without antagonizing its antitumor effects. Accordingly, we suggest that TXNIP is the key cause of ensartinib-induced hepatotoxicity and rutin is a potential clinically safe and feasible therapeutic strategy for TXNIP intervention.© 2024. The Author(s).