Crizotinib是一种小分子酪氨酸激酶抑制剂，针对ALK、MET和ROS1，是ALK阳性转移性非小细胞肺癌的一线药物，但与严重甚至致命的心力衰竭有关，增加了死亡风险。然而，其潜在机制尚不清楚，这导致缺乏治疗策略。我们建立了体外和体内模型来研究克唑替尼引起的心脏毒性，发现克唑替尼导致小鼠左心室功能障碍、心肌损伤和病理重构，并引发心肌细胞凋亡和线粒体损伤。此外，我们发现克唑替尼通过中断自噬体溶酶体融合而阻止MET蛋白的降解，并且MET的沉默或再激活巨噬自噬/自噬通量可以拯救克唑替尼引起的心肌细胞死亡和线粒体损伤，表明受损的自噬活性是克唑替尼引起的心脏毒性的关键原因。我们进一步证实，通过二甲双胍恢复PRKAA/AMPK的磷酸化（Ser485/491），可以在心肌细胞中重新激活自噬通量，并且二甲双胍可以拯救克唑替尼引起的心肌细胞损伤和心脏并发症。总之，我们揭示了克唑替尼引起心脏毒性的一种新机制，其中克唑替尼受损的自噬过程通过抑制MET蛋白的降解导致心肌细胞死亡和心肌损伤，证明了受阻的自噬体-溶酶体融合在药物引起的心脏毒性中的重要作用，并确认二甲双胍作为克唑替尼引起的心脏毒性的潜在治疗策略。

Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is associated with severe, sometimes fatal, cases of cardiac failure, which increases the risk of mortality. However, the underlying mechanism remains unclear, which causes the lack of therapeutic strategy. We established in vitro and in vivo models for crizotinib-induced cardiotoxicity and found that crizotinib caused left ventricular dysfunction, myocardial injury and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. In addition, we found that crizotinib prevented the degradation of MET protein by interrupting autophagosome-lysosome fusion and silence of MET or re-activating macroautophagy/autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib, suggesting that impaired autophagy activity is the key reason for crizotinib-induced cardiotoxicity. We further confirmed that recovering the phosphorylation of PRKAA/AMPK (Ser485/491) by metformin re-activated autophagy flux in cardiomyocytes and metformin rescued crizotinib-induced cardiomyocyte injury and cardiac complications. In summary, we revealed a novel mechanism for crizotinib-induced cardiotoxicity, wherein the crizotinib-impaired autophagy process causes cardiomyocyte death and cardiac injury by inhibiting the degradation of MET protein, demonstrated a new function of impeded autophagosome-lysosome fusion in drugs-induced cardiotoxicity, pointed out the essential role of the phosphorylation of PRKAA (Ser485/491) in autophagosome-lysosome fusion and confirmed metformin as a potential therapeutic strategy for crizotinib-induced cardiotoxicity.