Since the 21st century, the targeted cancer therapeutics, represented by the tyrosine kinase inhibitors (TKIs), have opened a new era of oncology.TKIs, designed to inhibit kinases that are mutated or over-expressed in cancer cells, have provided enhanced anti-tumor activity with less toxicity than traditional chemotherapies.However, with the wide and long-term clinical application, the majority of TKIs exerts unanticipated toxicities on the heart and other organs, and even threatened the life of patients.Although hERG channel toxicity, the most relevant drug-induced cardiotoxicity indicator, was not detected in preclinical drug safety evaluation of TKIs, serious cardiotoxicity still occur in clinic.Further study confirmed that TKIs-induced cardiotoxicity was not due to their own targets.Meanwhile, the mechanism of cardiotoxicity induced by traditional chemotherapy drugs such as doxorubicin was also irrelevant to TKIs-induced cardiotoxicity.Therefore, TKIs-induced cardiotoxicity might has very unique mechanism.Recently, our study focused on the mechanism of cardiotoxicity of TKIs has found that autophagy may play a critical role in TKIs cardiotoxicity, which will provide a new basis for the pathogenesis, risk assessment and prevention strategy of TKIs cardiotoxicity.Among 27 TKIs approved by the Food and Drug Administration (FDA), we performed an analogy study by selecting 8 TKIs with obvious cardiotoxicity and 1 TKIs with non-cardiotoxicity.We found that autophagy is critical for TKIs-induced cardiac toxic effects.However, TKIs also induce autophagy in liver cells, which could protect against its hepatotoxicity.Therefore, blocking autophagy by pan autophagy inbibitors could alleviate TKIs-induced cardiotoxity, but may also increase their hepatotoxicity.Thus, we chose sunitinib (one of TKIs with the most serious cardiotoxicity) to further explore the specific mechanism of autophagy-mediated cardiotoxicity.The activation of the key autophagy regulator HMGB1 by sunitinib is the vital signaling event of autophagy-induced cardiotoxicity.Sunitinib-increased HMGB1 activates JNK andpromotes the phosphorylation of Bcl2 , which blocks the interaction between Bcl2 and Beclin1, and finally results in the initiation of autophagy.Of note, inhibiting the expression of HMGB1 can specifically block sunitinib-induced autophagy in cadiomyocytes, thus alleviates the cardiotoxicity.All the above results reveal the possibility by targeting HMGB1 to predict and prevent sunitinib-induced cardiotoxicity.Furthermore, we discussed the molecular signaling pathways between the molecular initiating event-autophagy and adverse outcome-cardiotoxicity: the reasons of autophagy-caused cardiotoxicity.Mass spectrometry analysis results indicted that CTGF protein is accumulated in lysosomes upon sunitinib treatment.Sunitinib can induce autophagy and selectively trigger CTGF transfer into autolysosome for degradation and finally leads to cardiac injury.Inhibiting the autophagic degradation of CTGF in cadiomyocytes can obviously block the cardiotoxicity of sunitnib.Meanwhile, overexpression of CTGF in heart by adeno-associated virus can also significantly reverse sunitnib-induced cardiotoxicity, indicating that the autophagic degradation of CTGF is the key mechanism for sunitinib-induced cardiotoxicity.Moreover, HMGB1 can competitively block the interaction between autophagy Cargo protein Tollip and TLR2 / TLR4, which leads to Tollip interacts with CTGF and trigger CTGF transfer into the autolysosome for degradation.All these results reveal for the first time that autophagic degradation of CTGF regulated by HMGB1 is critical to sunitinib-induced cardiotoxicity, which enrich our understanding about TKIs-induced cardiotoxicity.