Doxorubicin has been indicated to be cardiotoxic and nephrotoxic, and thus it is often used as a model drug. Possible molecular mechanisms of this toxicity have been proposed, however, the systematic investigation of time-related metabolic trajectories specific to renal toxicity has rarely been reported. The present study was designed to assess time-dependent changes in doxorubicin-induced nephropathy through urinary metabolomics and to reveal the molecular mechanism based on key pathways. Urinary metabolomics revealed that the 14th day was the critical time point for model construction. Pathway analysis results showed that 5 pathways with impact (>0.01), FDR (<0.1) and p value (<0.05) were important. Furthermore, three pathways, including butanoate metabolism, alanine, aspartate and glutamate metabolism and arginine and proline metabolism, were focused on and validated by partial least squares regression analysis (PLS-RA) and molecular docking techniques. Our findings also showed that robust metabolomics combined with PLS-RA and molecular docking techniques is promising for elucidating time-dependent changes due to doxorubicin toxicity and for clarifying mechanisms, and the results provide a research foundation for the construction of a nephropathy model.

中文翻译：

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阐明阿霉素诱导的肾毒性下尿代谢组的时间依赖性变化

多柔比星已被证明具有心脏毒性和肾毒性，因此它经常被用作模型药物。已经提出了这种毒性的可能分子机制，然而，很少有关于肾毒性特异性时间相关代谢轨迹的系统研究的报道。本研究旨在通过尿液代谢组学评估多柔比星诱导的肾病的时间依赖性变化，并揭示基于关键途径的分子机制。尿液代谢组学显示，第 14 天是模型构建的关键时间点。通路分析结果显示有影响（>0.01）、FDR（<0.1）和p值（<0.05）的5条通路是重要的。此外，三种途径，包括丁酸代谢、丙氨酸、天冬氨酸和谷氨酸代谢以及精氨酸和脯氨酸代谢，通过偏最小二乘回归分析 (PLS-RA) 和分子对接技术得到关注和验证。我们的研究结果还表明，稳健的代谢组学结合 PLS-RA 和分子对接技术有希望阐明由于阿霉素毒性引起的时间依赖性变化并阐明机制，该结果为肾病模型的构建提供了研究基础。