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PKM2 crotonylation reprograms glycolysis in VSMCs, contributing to phenotypic switching

Oncogene volume 44, pages 1990–2003 (2025)Cite this article

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Abstract

Post-translational modifications (PTMs) of pyruvate kinase M2 (PKM2) play a vital role in regulating its activity and function. Recently, we found PKM2 can undergo crotonylation in vascular smooth muscle cell (VSMC) phenotypic switching. However, the role of PKM2 crotonylation remains unknown. Here, we verify a crucial role of PKM2 crotonylation in VSMC metabolic reprogramming. In PDGF-BB-induced synthetic VSMCs, PKM2 crotonylation was upregulated and promotes its nuclear translocation, thereby facilitating the expression of Glut1 and Ldha. Furthermore, crotonylation facilitated the dimeric formation of PKM2. Then we identified the highly conserved crotonylation site at K305 across different species. The crotonylation of PKM2 was compromised by PKM2 K305 mutation, resulting in the suppression of PKM2 dimeric configuration and nuclear relocation, and ultimately reducing glycolysis rate. Furthermore, PKM2 K305 crotonylation was necessary for VSMC phenotypic switching in vitro and intimal hyperplasia in vivo via infection of PKM2 recombinant adenovirus. In summary, PKM2 K305 crotonylation facilitates VSMC aerobic glycolysis by enhancing PKM2 dimeric form.

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Fig. 1: The crotonylation of PKM2 increased in the synthetic VSMCs.
Fig. 2: Crotonylation of PKM2 is associated with its nucleus translocation and the mRNA expression of Glut1 and Ldha.
Fig. 3: Crotonylation promotes the dimer formation of PKM2.
Fig. 4: Structural analysis of the PKM2 crotonylated sites.
Fig. 5: The dimer formation of PKM2 and nuclear translocation are dependent on the crotonylation at K305.
Fig. 6: PKM2 crotonylation reprograms glycolysis in VSMCs.
Fig. 7: Mutation at K305 of PKM2 attenuated neointima formation in vivo.

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All data needed to evaluate the conclusions in the paper are present in the paper and the supplementary information files.

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Acknowledgements

We thanked the support of the financial support from the Postdoctoral Fund of Hebei Medical University.

Funding

This work was supported by the Central Guidance for Local Scientific and Technological Development Funding Project (236Z7707G), the Hebei Natural Science Foundation (H202206335), Key laboratory of Neural and Vascular Biology, Ministry of Education of China (NV20210001) and the China Hebei International Joint Research Center for Structural Heart Disease; S&T Program of Hebei (22377719D).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Vascular Biology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

    Shan-Hu Cao, Ru-Yuan Ma, Tong Cao, Tao Hu, Shu Yang, Zhi-Yan Ren, Jiang-Ling Niu, Mei Han & Li-Hua Dong

  2. Department of Cardiology, Hebei Key Laboratory of Heart and Metabolism, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China

    Shan-Hu Cao & Ming-Qi Zheng

  3. Hebei Medical University Clinical Medicine Postdoctoral Mobile Station, Shijiazhuang, China

    Shan-Hu Cao

  4. Hebei Medical University, Shijiazhuang, China

    Li-Hua Dong

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Contributions

SC, LD and MH designed experiments. SC, RM, and TC contributed to conduct most of the experiments and analyzed data. ZR, JN and MZ assisted in the experiments. LD and MZ contributed to the fundings. SC, RM, and TC generated the illustrations. SC and LD wrote and edited the manuscript. TH and SY conducted a significant amount of work during the supplementary experiments. All authors reviewed and approved the final version of the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Ming-Qi Zheng, Mei Han or Li-Hua Dong.

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Cao, SH., Ma, RY., Cao, T. et al. PKM2 crotonylation reprograms glycolysis in VSMCs, contributing to phenotypic switching. Oncogene 44, 1990–2003 (2025). https://doi.org/10.1038/s41388-025-03353-9

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