非靶向代谢组学预测颅内肿瘤患儿甲氨蝶呤的排泄延迟

doi:10.5246/jcps.2026.04.022

中国药学(英文版) ›› 2026, Vol. 35 ›› Issue (4): 329-339.DOI: 10.5246/jcps.2026.04.022

• 【研究论文】 •

非靶向代谢组学预测颅内肿瘤患儿甲氨蝶呤的排泄延迟

时正媛¹^,²^,^*(), 杨春静¹^,², 续茜桥¹^,², 李京峰¹^,², 宝丽¹^,²

^1. 首都医科大学附属北京世纪坛医院药学部, 北京 100038
^2. 临床合理用药生物特征谱学评价北京市重点实验室, 北京 100038

收稿日期:2026-01-08 修回日期:2026-02-24 接受日期:2026-03-06 出版日期:2026-05-05 发布日期:2026-05-07
通讯作者: 时正媛

Untargeted metabolomics predicts delayed elimination of methotrexate in pediatric patients with intracranial tumors

Zhengyuan Shi¹^,²^,^*(), Chunjing Yang¹^,², Xiqiao Xu¹^,², Jingfeng Li¹^,², Li Bao¹^,²

^1. Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
^2. Beijing Key Laboratory of Bio-Characteristic Profiling for Evaluation of Clinical Rational Drug Use, Beijing 100038, China

Received:2026-01-08 Revised:2026-02-24 Accepted:2026-03-06 Online:2026-05-05 Published:2026-05-07
Contact: Zhengyuan Shi
Supported by:
Science and Technology Fund of Beijing Shijitan Hospital (Grant No. 2022-C06).

摘要/Abstract

摘要：

本研究旨在基于非靶向代谢组学技术筛选接受HDMTX化疗的儿童颅内肿瘤生物标志物, 为排泄延迟提供早期预警。采用超高效液相色谱-四极杆串联飞行时间质谱(UPLC-QTOF-MS/MS), 对髓母细胞瘤患儿给药前的血清样本进行分析。数据分析采用OPLS-DA的模式识别方法, 以区分甲氨蝶呤排泄正常组和延迟组之间代谢模式的差异, 共筛选血清样本中48种不同的代谢物。代谢途径分析结果显示, 正常排泄组和排泄延迟组的鞘脂代谢和甘油磷脂代谢存在显著差异。满足AUC大于0.8的10种差异代谢物被鉴定为用于进一步验证的候选生物标志物。本研究筛选的生物标志物可以区分甲氨蝶呤的正常排泄组和延迟排泄组, 可以作为甲氨蝶呤排泄延迟早期预警的潜在生物标志物。

关键词: 非靶向代谢组学, 儿童颅内肿瘤, 大剂量甲氨蝶呤, 排泄延迟, 生物标志物

Abstract:

This study aimed to identify biomarkers associated with intracranial tumors in children undergoing high-dose methotrexate (HDMTX) chemotherapy, using untargeted metabolomics to enable early detection of delayed drug elimination. Leveraging ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS/MS), serum samples from children with medulloblastoma were analyzed prior to drug administration. We developed an orthogonal partial least squares discriminant analysis (OPLS-DA)–based pattern recognition approach to characterize differences in metabolic profiles between children exhibiting normal MTX elimination and those with delayed elimination. A total of 48 distinct serum metabolites were identified. Metabolic pathway analysis revealed significant perturbations in sphingolipid and glycerophospholipid metabolism between the two groups. Among these, 10 differential metabolites demonstrated an AUC > 0.8 and were thus selected as candidate biomarkers for further validation. The biomarkers identified in this study effectively distinguished between normal and delayed MTX elimination, providing a potential early-warning tool for delayed drug clearance.

Key words: Untargeted metabolomics, Intracranial tumor in children, High-dose methotrexate, Delayed elimination, Biomarker

Supporting:

时正媛, 杨春静, 续茜桥, 李京峰, 宝丽. 非靶向代谢组学预测颅内肿瘤患儿甲氨蝶呤的排泄延迟[J]. 中国药学(英文版), 2026, 35(4): 329-339.

Zhengyuan Shi, Chunjing Yang, Xiqiao Xu, Jingfeng Li, Li Bao. Untargeted metabolomics predicts delayed elimination of methotrexate in pediatric patients with intracranial tumors[J]. Journal of Chinese Pharmaceutical Sciences, 2026, 35(4): 329-339.

图/表 8

Table 1. Clinical characteristics of the patient cohort.

Figure 1. PCA in positive-ion mode (A) and negative-ion mode (B) (QC represents quality control samples).

Figure 2. OPLS-DA score plots in positive-ion mode (A), OPLS-DA score plots in negative-ion mode (B), Permutation Test in positive-ion mode (C), and Permutation Test in negative-ion mode (D) between the normal elimination group and the delayed elimination group (NE represents the normal elimination group and DE represents the delayed elimination group samples).

Figure 3. FC (A) and VIP scores (B) representing the most contributing metabolites involved in separating the normal elimination group and the delayed elimination group.

Table 2. Identification of metabolites between the normal elimination group and the delayed elimination group.

Figure 4. Summary plot for pathway analysis in serum samples.

Figure 5. Heatmap of potential biomarkers in serum. The darker red color indicates the higher expression level of the metabolite, and the darker blue color indicates the lower expression.

Figure 6. ROC curves of the integrated biomarker.

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非靶向代谢组学预测颅内肿瘤患儿甲氨蝶呤的排泄延迟

Untargeted metabolomics predicts delayed elimination of methotrexate in pediatric patients with intracranial tumors

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