Fig. 3

Mechanisms of SMKIs-induced cardiotoxicity. Osimertinib exhibits simultaneous inhibition of the hERG potassium channel, Nav1.5 sodium channel, and L-type Ca²⁺ channel, all of which are involved in myocardial cell conduction. This inhibition leads to the prolongation of both the PR interval and QT interval. Afatinib specifically targets the EGFR and HER2 receptors, resulting in the blockade of the PI3K/AKT pathway. This blockade subsequently leads to the accumulation of ROS and the initiation of cell apoptosis, resulting in mitochondrial damage, ultimately inducing heart failure. Moreover, lapatinib also induces oxidative stress in myocardial cells through the PI3K/AKT pathway, further contributing to cardiotoxicity. Lastly, TKIs such as sorafenib or sunitinib selectively target the VEGFR and PDGFR receptors. Hypertension is a prevalent cardiotoxicity associated with VEGFR inhibitors, primarily attributed to the inhibition of downstream signaling pathways, such as ERK/AKT, after VEGF inhibition. This inhibition results in a reduction in the production of NOS and NO by endothelial cells, leading to vasoconstriction and the eventual development of hypertension. Furthermore, elevated blood pressure imposes an increased afterload on the heart, exacerbating cardiotoxicity. Additionally, following sorafenib treatment, there is an observed elevation in ATF3 expression within myocardial cells, which inhibits the expression of SLC7A11 and promotes ferroptosis of myocardial cells, resulting in cardiotoxicity. Imatinib induces cardiotoxicity by promoting endoplasmic reticulum (ER) stress and mitochondrial dysfunction, and ponatinib induces cardiomyocyte apoptosis by inhibiting the AKT/ERK signaling pathway, leading to cardiotoxicity. EGFR: epidermal growth factor receptor; HER2: human epidermal growth factor receptor 2; ROS: reactive oxygen species; TKIs: tyrosine kinase inhibitors; PDGFR: platelet-derived growth factor receptor; NOS: nitric oxide synthase; NO: nitric oxide; ER: endoplasmic reticulum