Doxorubicin（DOX）是一种用于多种癌症类型的强效化疗药物。然而，由于其心脏毒性副作用，使用该药物可能危及生命。尽管大多数癌症患者都是年长者，但他们在临床前和临床研究中的代表性和评估程度都很差。鉴于此，本研究旨在使用一种创新方法评估炎症和氧化应激作为DOX诱导的心脏毒性的主要机制，该方法采用了由接受临床相关的DOX累积剂量处理的老年动物构成的实验模型。老年（18-20个月）CD-1雄性小鼠每两周接受一次DOX给药，连续3周，以达到累积剂量为9.0mg/kg。最后一次DOX给药后1周（1W）或2个月（2M），收集心脏，以确定药物对心脏的短期和长期不良影响。所得结果显示，DOX会在两个时间点引起心脏组织学损伤和纤维化。在1W-DOX组中，核因子kappa B（NF-κB）p65免疫阳性细胞数量增加，并且NF-κB p65表达趋势增加。DOX后观察到诱导型一氧化氮合酶（iNOS）和白细胞介素（IL）-33的增加，IL-6和B细胞淋巴瘤2相关X（Bax）的表达趋势增加。在同一组中，观察到IL-1β，p62和微管相关蛋白1A / 1B-轻链3（LC3）-I以及p38丝裂原活化蛋白激酶（MAPK）表达的下降。相反，DOX后2M牺牲的动物显示了谷胱甘肽过氧化物酶1和Bax表达的显著增加，持续的心脏损伤和纤维化，而酮氨酸蛋白，红细胞相关因子2（Nrf2），NF-κB p65，髓过氧化酶，LC3-I和LC3-II的表达减少。总之，我们的研究证明，在老年小鼠群体中，DOX在短期内会引起心脏炎症、自噬和凋亡。当长期保持时，氧化应激相关途径仍然改变，自噬标记物和DOX治疗后的组织损伤，强调了对持续治疗后心脏的监测的需求。© 2023 作者。

Doxorubicin (DOX) is a potent chemotherapeutic agent used against several cancer types. However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18-20 months) CD-1 male mice received biweekly DOX administrations, for 3 weeks, to reach a cumulative dose of 9.0 mg/kg. One week (1W) or two months (2 M) after the last DOX administration, the heart was collected to determine both drug's short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-κB) p65 immunopositive cells increased and a trend toward increased NF-κB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1β, p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2 M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-κB p65, myeloperoxidase, LC3-I, and LC3-II expression decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment cardiac monitoring.© 2023. The Author(s).