Doxorubicin, a commonly used anti-neoplastic agent, causes severe neurotoxicity. Doxorubicin promotes thinning of the brain cortex and accelerates brain aging, leading to cognitive impairment. Oxidative stress induced by doxorubicin contributes to cellular damage. In addition to mitochondria, peroxisomes also generate reactive oxygen species (ROS) and promote cell senescence. Here, we investigated if doxorubicin affects peroxisomal homeostasis in neurons. We demonstrate that the number of peroxisomes is increased in doxorubicin-treated neurons and in the brains of mice which underwent doxorubicin-based chemotherapy. Pexophagy, the specific autophagy of peroxisomes, is downregulated in neurons, and peroxisomes produce more ROS. 2-hydroxypropyl-β-cyclodextrin (HPβCD), an activator of the transcription factor TFEB, which regulates expression of genes involved in autophagy and lysosome function, mitigates damage of pexophagy and decreases ROS production induced by doxorubicin. We conclude that peroxisome-associated oxidative stress induced by doxorubicin may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. Peroxisomes might be a valuable new target for mitigating neuronal damage caused by chemotherapy drugs and for slowing down brain aging in general.

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过氧化物酶体在基于阿霉素的化学疗法中促进神经元的氧化应激。

阿霉素，一种常用的抗肿瘤药，会引起严重的神经毒性。阿霉素可促进大脑皮层变薄并加速大脑衰老，从而导致认知障碍。阿霉素诱导的氧化应激导致细胞损伤。除线粒体外，过氧化物酶体还产生活性氧（ROS）并促进细胞衰老。在这里，我们调查了阿霉素是否会影响神经元的过氧化物酶体稳态。我们证明过氧化物酶体的数量在阿霉素治疗的神经元和接受基于阿霉素的化学疗法的小鼠的大脑中增加。过氧化物酶体是过氧化物酶体的特异性自噬，在神经元中被下调，并且过氧化物酶体产生更多的ROS。2-羟丙基-β-环糊精（HPβCD），转录因子TFEB的激活剂，它调节涉及自噬和溶酶体功能的基因的表达，减轻exexophagy的损害并减少由阿霉素诱导的ROS产生。我们得出的结论是，阿霉素诱导的与过氧化物酶体相关的氧化应激可能会导致神经毒性，认知功能障碍以及加速癌症患者和幸存者的大脑衰老。过氧化物酶体可能是减轻化疗药物引起的神经元损害并总体上减缓脑部衰老的有价值的新靶标。