Limitations of Ferroptosis Inhibitors on the Doxorubicin-Induced Cardiotoxicity Yun-Ji Cha, Sae-Bom Jeon, Chan Joo Lee, Hyeong-Jin Kim, Sun-Ho Lee, et al. Antioxidants, 2026 Doxorubicin is an anthracycline anticancer drug commonly used to treat lymphoma and breast cancer. Its major side effect is cardiotoxicity, which occurs by damaging cardiomyocytes. The mechanisms of doxorubicin-induced cardiotoxicity remain unclear; however, recent studies suggest that ferroptosis, an iron-dependent form of lipid peroxidation-mediated cell death, may play a key role. In this study, we investigated the role of ferroptosis in doxorubicin-induced cardiotoxicity using ferroptosis-specific inhibitors (ferrostatin-1 and liproxstatin-1). In both H9c2 cardiomyocyte cell lines and human induced pluripotent stem cell-derived cardiomyocytes, ferrostatin-1 and liproxstatin-1 rescued cell death induced by RSL3, a ferroptosis inducer, but failed to prevent doxorubicin-induced cell death. Additionally, the ferroptosis inhibitors did not restore the electrophysiological function of cardiomyocytes, measured using a multi-electrode array system, and instead slightly accelerated cardiomyocyte beating. Finally, doxorubicin-injected mice treated with ferroptosis inhibitors exhibited significantly reduced survival and increased levels of N-terminal pro B-type natriuretic peptide, a biomarker of heart failure. These findings suggest that inhibiting ferroptosis alone is insufficient to mitigate doxorubicin-induced cardiotoxicity.
Inhibition of TBL1 cleavage alleviates doxorubicin-induced cardiomyocytes death by regulating the Wnt/β-catenin signal pathway Sun-Ho Lee, Jangho Lee, Jaewon Oh, Jin-Taek Hwang, Hae-Jeung Lee, et al. Cardiovascular Research, 2024 Aims Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. Methods and results We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites—D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with β-catenin. As a result, Wnt reporter activity and Wnt target gene expression collectively indicate a decrease in Wnt/β-catenin signalling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. Conclusion Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT.
Resveratrol downregulates acetyl-CoA carboxylase α and fatty acid synthase by AMPK-mediated downregulation of mTOR in breast cancer cells Food Science and Biotechnology, 2008
