ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing Slc7a11 expression

Abstract

Sorafenib is the unique recommended molecular-targeted drug for advanced hepatocellular carcinoma, but its clinical use is limited due to cardiotoxicity. As sorafenib is an efficient ferroptosis inducer, the pathogenesis of this compound to ferroptosis-mediated cardiotoxicity is worth further study. Mice were administered 30 mg/kg sorafenib intraperitoneally for 2 weeks to induce cardiac dysfunction and Ferrostatin-1 (Fer-1) was used to reduce ferroptosis of mice with sorafenib-induced cardiotoxicity. Sorafenib reduced levels of anti-ferroptotic markers involving Slc7a11 and glutathione peroxidase 4 (GPX4), increased malonaldehyde malondialdehyde, apart from causing obvious mitochondria damage, which was alleviated by Fer-1. In vitro experiments showed that Fer-1 inhibited lipid peroxidation and injury of H9c2 cardiomyoblasts induced by sorafenib. Both in vitro and in vivo experiments confirmed that the expression of Slc7a11 was down regulated in sorafenib-induced cardiotoxicity, which can be partially prevented by treatment with Fer-1. Overexpression of Slc7a11 protected cells from ferroptosis, while knock-down of Slc7a11 made cardiomyoblasts sensitive to ferroptosis caused by sorafenib. Finally, by comparing data from the GEO database, we found that the expression of ATF3 was significantly increased in sorafenib treated human cardiomyocytes. In addition, we demonstrated that ATF3 suppressed Slc7a11 expression and promoted ferroptosis. Based on these findings, we concluded that ATF3/Slc7a11 mediated ferroptosis is one of the key mechanisms leading to sorafenib-induced cardiotoxicity. Targeting ferroptosis may be a novel therapeutic approach for preventing sorafenib-induced cardiotoxicity in the future.

Knockdown of ATF3 suppresses the progression of ischemic stroke through inhibiting ferroptosis

“…Notably, ATF3 plays an important role in regulating ferroptosis, arousing our great attention. For example, Li et al have shown that sorafenib induces ferroptosis-mediated cardiotoxicity in mice ( Li Y. et al, 2022 ). Wang et al have found that quercetin relieves acute kidney injury through inhibiting ATF3-mediated ferroptosis ( Wang Y. et al, 2021 ).…”

Effective detection of BRAFV595E mutation in canine urothelial and prostate carcinomas using immunohistochemistry

“…In contrast to human tumours and the one investigated human cell line in their study, canine cell lines were more sensitive to sorafenib than vemurafenib 10 . Sorafenib is an important drug for liver cancer therapy in men, primarily through the induction of apoptosis and ferroptosis and it is not a specific BRAF inhibitor, in contrast to vemurafenib 43 . As Jung and colleagues suggest, the different sensitivity of BRAF mutant cancer to sorafenib and vemurafenib in men and dogs may indicate different cancer genetics in men and dogs, innate resistance to vemurafenib in canines, or different drug binding affinity to the BRAF protein in humans and dogs.…”

Sialyltransferase7A promotes cardiomyocyte ferroptosis induced by sorafenibthrough increase in HIF-1ɑ expression

“…So how does sorafenib realize the process of inducing ferroptosis of cardiac cells? Li et al reported that ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing SLC7A11 expression [9]. Jiang et al reported that ATF4 protects against sorafenib-induced cardiotoxicity by suppressing ferroptosis [10].…”

“…Sorafenib is reported to cause ferroptosis during hepatocellular carcinoma therapy through inhibiting cystine/glutamate antiporter system Xcactivity [8]. Recent studies revealed the critical role of ferroptosis in sorafenib induced cardiotoxicity [9,10].…”