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Genetics and Genomics

Metabolic dysregulation associated with core symptom cluster in lung cancer patients undergoing chemotherapy

British Journal of Cancer volume 134, pages 295–305 (2026)Cite this article

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Abstract

Background

Adverse symptoms are the main reason for unexpected hospital admissions in lung cancer patients. The fatigue-pain-sleep disturbance symptom cluster is the core symptom cluster among those undergoing chemotherapy, significantly affecting the clinical outcomes of patients. The mechanisms behind the core symptom cluster haven’t been well understood and may relate to metabolic disorders. Understanding the related mechanisms is crucial for symptom management and patient outcomes.

Methods

One hundred lung cancer patients undergoing chemotherapy were involved in this cross-sectional study. During their third to fifth chemotherapy, they were asked to complete questionnaires that evaluated the condition of fatigue, pain, and sleep disturbance. Patients were categorized into high, moderate, and low core symptom cluster groups using the K-means algorithm. Comparison was conducted on demographic data, symptoms, and symptom interference among groups. Plasma samples from patients were collected for untargeted metabolomics, and the differential metabolites among groups were identified. Pathway enrichment analysis was performed to understand the potential mechanism of the core symptom cluster. Trend analysis was conducted on the differential metabolites to identify the significant clusters of metabolites with similar variation among groups. Receiver Operating Characteristic curves were generated to evaluate the distinguish efficacy of the metabolites panel for the core symptom cluster.

Results

The K-means algorithm categorized 100 patients into three groups based on core symptom cluster, including 46 in low, 35 in moderate, and 19 in high. Most of the cancer-related symptoms and symptom interference were increased progressively with the severity of the core symptom cluster. The metabolomic analysis identified 1,334 annotated metabolites. The high and moderate groups showed a higher similarity in metabolic profile, yet were distinct from the low group. Choline metabolism in cancer was the highest enrichment pathway in the Kyoto Encyclopedia of Genes and Genomes analysis. Trend analysis identified a panel of 24 metabolites that increased with core symptom cluster progression, distinguishing 87.8% of patients with moderate or high severity from those with low.

Conclusions

This study is the first to explore the metabolic profile associated with the core symptom cluster in lung cancer, revealing significant changes in the clinical phenotypes and metabolic disorders in patients with moderate to high core symptom cluster. Dysregulated choline metabolism emerged as a key signature within the broader metabolic disturbances linked to core symptom cluster. We identified a promising panel of metabolites for diagnosing the core symptom cluster, which are expected to serve as biomarkers in the future.

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Fig. 1: K-means algorithm clusters patients into three subgroups: low, moderate, and high-CSC based on the CSC score.
Fig. 2: Comparative analysis of symptom burden and interference among groups.
Fig. 3: Comparison of metabolic characteristics among groups.
Fig. 4: Dynamic trend analysis of differential metabolites among groups.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Code availability

All analyses central to this study were performed with publicly available software packages whose versions are documented in the Methods section. No custom code was generated beyond routine parameter settings within programs.

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Funding

The work was supported by the National Natural Science Foundation of China (No. 72374097). The funders had no role in study design, data analysis, or decision to publish.

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Author notes

  1. These authors contributed equally: Yanxuan Xiao, Yuanyuan Luo, Dongmei Mao.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

    Yanxuan Xiao & Zhijian Wang

  2. School of Nursing, Southern Medical University, Guangzhou, China

    Yanxuan Xiao, Yuanyuan Luo, Dongmei Mao, Le Zhang, Ruiyan Bai, Zhihui Yang, Yang Zhao, Fengyi Zhang & Lili Zhang

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  1. Yanxuan Xiao
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Contributions

ZW and LZ designed the study and obtained grant support; YX and YL conducted the experiments; DM, Le Z, RB, ZY, YZ, and FZ recruited the patients and collected samples; YX performed data analysis and wrote the manuscript. All authors saw and approved the final version, and no other person made a substantial contribution to the paper.

Corresponding authors

Correspondence to Lili Zhang or Zhijian Wang.

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The authors declare no competing interests.

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This research has been approved by The Research Ethics Board of Nanfang Hospital of Southern Medical University (NFEC-202312-K6), and all patients have signed the informed consent.

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Xiao, Y., Luo, Y., Mao, D. et al. Metabolic dysregulation associated with core symptom cluster in lung cancer patients undergoing chemotherapy. Br J Cancer 134, 295–305 (2026). https://doi.org/10.1038/s41416-025-03262-4

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