Rutin attenuates ensartinib-induced hepatotoxicity by non-transcriptional regulation of TXNIP.

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.

Dihydroartemisinin alleviates hepatic fibrosis through inducing ferroptosis in hepatic stellate cells.

Targeting the elimination of activated hepatic stellate cells (HSCs) and blocking excessive deposition of extracellular matrix are recognized as an effective strategy for the treatment of hepatic fibrosis. As a newly discovered programmed cell death mode, the regulatory mechanism of ferroptosis in the clearance of activated HSCs has not been fully elucidated. In the present study, we reported that the induction of ferroptosis in activated HSCs was required for dihydroartemisinin (DHA) to alleviate hepatic fibrosis. Treatment with DHA could improve the damage of hepatic fibrosis in vivo and inhibit the activation of HSCs in vitro. Interestingly, DHA treatment could trigger ferroptosis to eliminate activated HSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Specific ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 could impair DHA-induced ferroptosis and also damage DHA-mediated the inhibition of activated HSCs. Importantly, autophagy activation may be closely related to DHA-induced ferroptosis. ATG5 siRNA could prevent DHA-mediated autophagy activation and ferroptosis induction, whereas ATG5 plasmid could promote the effect of DHA on autophagy and ferroptosis. Of note, the upregulation of nuclear receptor coactivator 4 (NCOA4) may play a critical role in the molecular mechanism. NCOA4 siRNA could impair DHA-induced ferroptosis, whereas NCOA4 plasmid could enhance the promoting effect of DHA on ferroptosis. Overall, our study revealed the potential mechanism of DHA against hepatic fibrosis and showed that ferroptosis could be a new way to eliminate activated HSCs.