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Targeting PPARĪ± activation sensitizes glioblastoma cells to temozolomide and reverses acquired resistance by inhibiting H3K18 lactylation

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Temozolomide (TMZ) is an alkylating agent recommended as the first-line pharmaceutical for glioblastoma (GBM), but its efficacy is limited by the development of acquired resistance in GBM cells. TMZ resistance is regulated by multiple factors such as MGMT upregulation and metabolism reprogramming, its underlying mechanism still remains elusive. Peroxisome proliferator-activated receptor alpha (PPARĪ±) is a transcription factor regulating the metabolism of lipid and glucose, while histone 3 lactylation at lysine on position 18 (H3K18la) could promote cancer cellsā€™ resistance to therapeutic drugs. In this study we investigated the role of PPARĪ± in regulating H3K18la and TMZ sensitivity in glioblastoma (GBM) cells. We established TMZ-resistant U87TR, U251TR, and U118TR cells by treating the parental U87, U251, and U118 cells with increased dosages of TMZ until the cells could resist TMZ (200ā€‰Ī¼M). We found that in TMZ-resistant cells, H3K18la level was apparently upregulated accompanied by increased ECAR (extracellular acidification rate) and intracellular lactate levels, whereas lactate (20ā€‰mM) time-dependently upregulated H3K18la in U87 and U251 cells. We found that PPARĪ± was activated by TMZ in U87, U251, and U118 cells, but was inactivated when the cells became resistant to TMZ. In TMZ-sensitive glioma cells, TMZ triggered PPARĪ± activation by causing DNA DSBs-dependent p38 MAPK activation. The activated PPARĪ± upregulated its downstream signal ACOX1, which not only inhibited lactate-mediated H3K18 lactylation by promoting ROS-dependent PKM2 downregulation, but also reversely enhanced PPARĪ± activation through ROS-activated ASK1/p38 MAPK pathway. In GBM cells resistant to TMZ, PPARĪ± and p38 MAPK were both inactivated, but H3K18 lactylation was obviously upregulated. Targeting activation of PPARĪ± with gemfibrozil or GW7647 not only sensitized GBM cells to TMZ but also effectively reversed the acquired resistance of GBM cells to TMZ by suppression of H3K18 lactylation through upregulation of ACOX1. Taken together, PPARĪ± contributed to TMZ-induced growth arrest in GBM cells by inhibiting lactate-mediated H3K18 lactylation, targeting activation of PPARĪ± may be a new strategy to improve the treatment effect of TMZ against GBM.

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Fig. 1: H3K18 lactylation promoted GBM cell resistance to TMZ.
Fig. 2: PPARĪ± inhibited H3K18 lactylation by depleting lactate.
Fig. 3: PPARĪ± depleted lactate by suppressing PKM2-dependent pyruvate generation.
Fig. 4: ACOX1 contributed to PPARĪ±-dependent PKM2 downregulation by increasing ROS.
Fig. 5: ACOX1 promoted p38 MAPK activation via the ASK1 pathway.
Fig. 6: Targeting PPARĪ± activation reversed H3K18la upregulation in TMZ-resistant GBM cells.
Fig. 7: In vivo study.
Fig. 8: In vivo study.
Fig. 9: Schematic diagram.

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The authors declare that all the data underlying the study can be made available to readers upon request.

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Acknowledgements

This work was supported by the National Nature and Science Foundation of China (81972346, 82173027 and 82372690), the Scientific Research Foundation of Jilin Province (20230508060RC and 20240402001GH), and the Collaboration Fund of the First Hospital of Jilin University and the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences (2022YYGFZJC011).

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Authors and Affiliations

  1. Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China

    Zhen-chuan Wang,Ā Chen Li,Ā Zhao Zhang,Ā Shan Lu,Ā Peng Qi,Ā Yu-bo Wang,Ā Wen-jie Feng,Ā Cheng-liang Pan,Ā Qing-xuan Wang,Ā Zhi-lin Ji,Ā Ying YuĀ &Ā Peng-fei Ge

  2. Department of Pathology, First Hospital of Jilin University, Changchun, 130021, China

    Ying-min Liu

  3. Department of Neurosurgery, Second Hospital of Jilin University, Changchun, 130021, China

    Xi Chen

  4. Department of Anesthesiology, First Hospital of Jilin University, Changchun, 130021, China

    Mei-hua Piao

  5. Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China

    Guang-fan Chi

  6. Tumor Research Institute of Jilin University, First Hospital of Jilin University, Changchun, 130021, China

    Peng-fei Ge

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Contributions

PFG and ZCW conceived, designed, and interpreted the study. ZCW, CL, ZZ, SL, YML, PQ, XC,Ā YBW, WJF, CLP, QXW, and ZLJ undertook the data acquisition and analysis. YY, MHP, and GFC were responsible for comprehensive technical support. PFG and ZCW were major contributors to the writing of the manuscript. YY, MHP, and GFC contributed to the inspection of the data and the final manuscript. All the authors have read and approved the final manuscript.

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Correspondence to Peng-fei Ge.

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Wang, Zc., Li, C., Zhang, Z. et al. Targeting PPARĪ± activation sensitizes glioblastoma cells to temozolomide and reverses acquired resistance by inhibiting H3K18 lactylation. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01600-z

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