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ORIGINAL RESEARCH article

Front. Oncol.

Sec. Gastrointestinal Cancers: Colorectal Cancer

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1617207

This article is part of the Research TopicNational Colorectal Cancer Awareness Month 2025: Current Progress and Future Prospects on Colorectal Cancer Prevention, Diagnosis and TreatmentView all 14 articles

Metabolome profiling by untargeted metabolomics and biomarker panel selection using machine-learning for patients in different stages of peripheral neuropathy induced by oxaliplatin

Provisionally accepted
Yujiao  HuaYujiao Hua1,2Ying  ZhangYing Zhang3Ruirong  WuRuirong Wu3Juan  LvJuan Lv2Yan  ZhangYan Zhang1Yanyan  ChenYanyan Chen4*Yongjuan  DingYongjuan Ding2*Jinghua  ChenJinghua Chen1*
  • 1School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu Province, China
  • 2Department of Clinical Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
  • 3Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
  • 4Cancer Institute, Institute of Integrated Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China

The final, formatted version of the article will be published soon.

Background: Oxaliplatin-induced peripheral neuropathy (OIPN) poses a significant challenge for patients with colorectal tumor, often resulting in treatment interruption or discontinuation and subsequent treatment failure. Herein, a longitudinal untargeted metabolomic study to reveal the metabolomic profiles and biomarkers associated with the progression of OIPN. Methods: A prospective cohort of 129 colorectal cancer patients receiving oxaliplatin-based chemotherapy was stratified into four OIPN severity grades (Level 0-3). Serum samples underwent untargeted LC-MS/MS metabolomic analysis, detecting 521 metabolites. Multivariate statistical models and SHAP-guided random forest algorithms were employed to prioritize biomarkers. Machine learning validation included six classifiers assessed via ROC-AUC. Results: The cumulative dose of Oxaliplatin chemotherapy plays an important role in OIPN. At the same time, our findings implied that the occurrence of OIPN may be associated with the progression of the disease and the patients' tumor markers (CEA, CA19-9, CA72-4), as well as immune response and inflammation (ANC, PLT), and metabolic and liver function abnormalities (GGT and UA) (P<0.05).Multivariate statistical analysis combined with SHAP-guided machine learning identified six biomarkers, including thiabendazole, 1-methylxanthine, imidazol-5-yl-pyruvate, 5-hydroxypentanoic acid, spermidine, and 4'-oxolividamine that consistently distinguished OIPN patients (Level 1-3) from non-OIPN controls (Level 0). Machine learning models, validated across six classifiers, demonstrated near-perfect discrimination for early-stage OIPN (AUC nearly 1). However, differentiation between intermediate OIPN grades (Level 1 vs 2, Level 1 vs 3, Level 2 vs 3) yielded lower predictive accuracy (AUC: 0.549–0.843), likely due to cohort size limitations and reliance on subjective sensory-based grading. Pathway enrichment analysis highlighted dysregulation in ABC transporters, central carbon metabolism in cancer, amino acid metabolism, and linoleic acid metabolism, suggesting potential roles in OIPN pathogenesis. Conclusions: These findings suggest that the selected biomarkers could serve as a foundation for the prediction and management of OIPN in colorectal cancer patients.

Keywords: Oxaliplatin-induced peripheral neuropathy, biomarkers, Untargetedmetabolomics, machine-learning, colorectal cancer

Received: 24 Apr 2025; Accepted: 01 Sep 2025.

Copyright: © 2025 Hua, Zhang, Wu, Lv, Zhang, Chen, Ding and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Yanyan Chen, Cancer Institute, Institute of Integrated Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
Yongjuan Ding, Department of Clinical Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
Jinghua Chen, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, Jiangsu Province, China

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