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Chemotherapy induces multiple sclerosis-like neuropathologies that can be rescued by clobetasol

Cell Death & Differentiation (2025)Cite this article

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Abstract

Chemotherapy is essential for cancer management yet frequently accompanied with adverse effects, particularly for temozolomide (TMZ), a frontline chemotherapeutic agent for glioma. Although clinical neurological abnormalities linked to TMZ have been observed, mechanisms underlying TMZ-induced neural impairments remain poorly understood, and effective interventions are lacking. Here, we demonstrated that TMZ chemotherapy induced neurodegenerations that recapitulated pathological features of multiple sclerosis, including demyelination, neuroinflammation and axonal degeneration. In adolescent mice, TMZ treatment resulted in severe white matter damage that spontaneously recovered, whereas in adult mice, moderate myelin damage persisted without recovery within the same timeframe. Importantly, we identified that clobetasol effectively reversed TMZ-induced white matter damage and trends toward anxiety and depression in adult mice by suppressing TMZ-induced AMPK activation and attenuating neuroinflammation, thereby promoting remyelination. Our findings reveal the previously underappreciated neural toxicities associated with TMZ chemotherapy and highlight the therapeutic efficacy of clobetasol in mitigating chemotherapy-induced neural impairment, providing a strategy to enhance the life quality of cancer patients.

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Fig. 1: TMZ treatment clinically associates with neurological abnormalities.
Fig. 2: snRNA-seq reveals cellular alterations by TMZ in mouse cortex.
Fig. 3: TMZ induces demyelination in adolescent mice.
Fig. 4: TMZ induces neuroinflammation and axonal degeneration in adolescent mice.
Fig. 5: TMZ activates AMPK signaling in oligodendrocytes.
Fig. 6: Reversal of TMZ-induced neural pathologies by CBT in adult mice.
Fig. 7: Model.

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Data availability

All relevant materials, including the snRNA-seq and bulk RNA-seq data, are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Kunlong Zhang for the technical help on confocal imaging, and Dr. Shiping Liao, Zhangyu He and Baichuan Li for the support in mouse experiments.

Funding

This work was supported by grants from National Natural Science Foundation of China (No. 82272644 to Y.L., 82372836 to W.Y., and 81571195 to M.C.), and Sichuan Science and Technology Program (No. 2023YFQ0002 to Y.L. and 2023YFSY0042 to W.Y.).

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  1. These authors contributed equally: Qiuyun Yuan, Wanchun Yang, Siliang Chen.

Authors and Affiliations

  1. Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China

    Qiuyun Yuan, Wanchun Yang, Siliang Chen, Yunbo Yuan, Jingwen Gong, Tengfei Li, Mingrong Zuo, Yuze He, Zhihao Wang & Yanhui Liu

  2. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China

    Yuting Shu, Yue Qin, Xiaoqiang Xia, Yiyuan Cui & Mina Chen

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Contributions

Conceptualization: Qiuyun Yuan, Wanchun Yang, Yanhui Liu, Mina Chen. Methodology: Qiuyun Yuan, Wanchun Yang, Siliang Chen, Yunbo Yuan, Jingwen Gong, Yue Qin. Investigation: Qiuyun Yuan, Wanchun Yang, Siliang Chen, Jingwen Gong, Tengfei Li, Mingrong Zuo, Yuting Shu, Yuze He, Zhihao Wang, Xiaoqiang Xia, and Yiyuan Cui. Visualization: Qiuyun Yuan, Wanchun Yang, Siliang Chen, Yunbo Yuan. Funding acquisition: Wanchun Yang, Yanhui Liu and Mina Chen. Project administration: Yanhui Liu. Supervision: Yanhui Liu and Mina Chen. Writing – original draft: Qiuyun Yuan and Wanchun Yang. Writing – review & editing: Yanhui Liu and Mina Chen.

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Correspondence to Yanhui Liu or Mina Chen.

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All human studies were approved by the Institutional Review Board of West China Hospital of Sichuan University (No. 20241074) and all patients provided written informed consent. For animal works, ethical guidelines for animal experimentation were followed, with approval from the Institutional Animal Care and Use Committees of West China Hospital of Sichuan University (No. 20220228009).

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Yuan, Q., Yang, W., Chen, S. et al. Chemotherapy induces multiple sclerosis-like neuropathologies that can be rescued by clobetasol. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01635-z

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