Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN’s cardioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes’ resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflammatory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN’s cardioprotective potency against DIC based on its antioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy.

中文翻译：

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揭示双醋瑞因在阿霉素心脏毒性中的心脏保护潜力：通过上调 NRF2/SLC7A11/GPX4 轴减轻铁蛋白吞噬介导的铁死亡

阿霉素 (DOX) 引起的心脏毒性 (DIC) 是一个危及生命的临床问题，预防方法有限，给癌症幸存者带来了巨大的挑战。蒽醌双醋瑞因 (DCN) 具有显着的抗炎、抗增殖和抗氧化作用。它对 DIC 的有益作用尚未明确。因此，本研究调查了 DCN 的心脏保护功效及其针对 DIC 的可能分子靶标。将 28 只 Wister 大鼠分配至 CON、DOX、DCN-L/DOX 和 DCN-H/DOX 组。评估了血清心脏损伤指数、铁测定、氧化应激、炎症、内质网（ER）应激、细胞凋亡、铁蛋白自噬和铁死亡相关生物标志物。评估了核因子 E2 相关因子 2 (NRF2) DNA 结合活性和磷酸化 p53 免疫反应性。 DCN 给药有效改善了 DOX 诱导的心脏细胞形态学异常。此外，DCN 可以有效对抗 DOX 诱导的不稳定铁池扩张以及随之而来的致命的脂质过氧化物过量产生，同时它还可以抵消铁蛋白自噬并增强铁储存。事实上，DCN 主要通过恢复 NRF2/溶质载体家族 7 成员 11 (SLC7A11)/谷胱甘肽过氧化物酶 4 (GPX4) 信号轴，有效地增强了心肌细胞对铁死亡的抵抗力。此外，DCN 消除了 DOX 引起的心脏氧化损伤、炎症反应、内质网应激和心肌细胞凋亡。总之，我们的研究结果首次验证了 DCN 对 DIC 的心脏保护功效，这是基于其抗氧化、抗炎、抗铁死亡和抗凋亡印记，主要由 NRF2/SLC7A11/GPX4 轴介导。因此，DCN 可能为 DOX 依赖性化疗患者提供一种有前景的治疗途径。