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Cardiotoxicity is a critical side-effect of nilotinib during treatment for cancer, such as chronic myeloid leukemia, while the potential signaling mechanisms remain unclear. The role of and the relationship between endoplasmic reticulum (ER) stress and mitochondrial dysfunction was investigated in nilotinib-induced cardiac H9C2 injury as a suitable cell model. Our results showed that ER stress was persistently induced in nilotinib-treated cells, evidenced by increase of GRP78, CHOP, ATF4 and XBP1 as well as phospho-PERKThr980. The results from 4-phenylbutyrate (PBA, an ER stress inhibitor) and SC79 (a specific Akt activator) suggested that ER stress increased activity of glycogen synthase kinase-3 beta (GSK3β) that is reflected by decrease of phospho-GSK3βSer9, through downregulation of phospho-AktSer473, and that prolonged ER stress and activated GSK3β involved nilotinib-induced apoptosis. In addition, the data from JNK inhibition using SP600125 showed that over-activated JNK was responsible for Akt de-phosphorylation. Moreover, the abundance of NADPH oxidase (Nox4) was significantly increased following nilotinib treatment, which was prevented by SB216763 (a specific GSK3β inhibitor). Additionally, mitochondrial dysfunction was indicated by reduced mitochondrial membrane potential (MMP) level and increased reactive oxygen species level. In nilotinib-treated cells, knockdown of Nox4 preserved MMP level, abrogated reactive oxygen species production, and decreased apoptosis. Accordingly, our data demonstrated that inhibition of ER stress may protect cardiomyocytes against nilotinib toxicity potentially through inactivation of Akt-GSK3β-Nox4 signaling. These findings may provide an attractive therapeutic target for treatment of nilotinib-related cardiotoxicity.