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GRK2-mediated phosphorylation and de-succinylation of PKM2 reduce macrophage glycolysis in rheumatoid arthritis

Acta Pharmacologica Sinica volume 46, pages 2693–2706 (2025)Cite this article

Abstract

Glucose metabolism disorder is an important hallmark of rheumatoid arthritis (RA). Inhibiting key glycolysis enzymes is the primary approach, but effective treatments targeting glycolytic metabolism have not yet reached clinical practice. G protein-coupled receptor kinase 2 (GRK2) as a multi-signals regulatory hub has attracted wide attention. In this study, we investigated the role of GRK2 inhibitor on glycolysis of monocyte-derived macrophages (MDMs), the primary source of inflammatory mediators in RA synovium. Human peripheral mononuclear cells were obtained from RA patients and differentiated into MDMs with M-CSF (100 ng/ml) for 5 days. By analyzing the metabolic status of RA MDMs in normoxia and hypoxia, we found that glycolysis was increased in RA MDMs, and inhibiting glycolysis could suppress the macrophage inflammatory phenotype. The antiglycolytic role of GRK2 deletion was tested in MDMs in vitro and in vivo. We conducted proteomics and mass spectrometric analysis and confirmed the inhibitory role of GRK2 on several key glycolytic enzymes. GRK2 maintained PKM2 tetramer stability through two synergistic modifications—phosphorylation at S406 and de-succinylation at K433. In RA, decreased cytoplasmic GRK2 protein levels impaired its regulation toward PKM2, leading to enhanced glycolysis and accelerating RA progression. Administration of GRK2 inhibitors paroxetine, CP-25, or the glycolysis inhibitor 2-DG for 21 days in the CIA mouse model all restored cytoplasmic GRK2 levels and homeostatic regulation, offering a potential therapeutic approach for RA glycolysis.

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Fig. 1: Increased glycolysis of MDMs in RA.
Fig. 2: GRK2 deletion enhances glycolysis of BMDMs.
Fig. 3: Identification of PKM2 as a GRK2-binding protein.
Fig. 4: GRK2 determines PKM2 dimer/tetramer equilibrium.
Fig. 5: GRK2 promotes PKM2 phosphorylation and de-succinylation.
Fig. 6: GRK2 phosphorylates PKM2 at S406 and de-succinylates it at K433.
Fig. 7: GRK2 activity inhibitor restores GRK2-PKM2 interaction to reduce the glycolysis of CIA MDMs.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82473931, 82430114 and 82204405), the Natural Science Foundation of Anhui Provincial (No. 2408085MH217), the Young Elite Scientists Sponsorship Program of Anhui Association for Science and Technology (No. RCTJ202427), the Research Fund of Anhui Institute of translational medicine (No. 2022zhyx-B04), and the Anhui Province Excellent Research and Innovation Team Project (No. 2024AH010013).

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  1. These authors contributed equally: Xue-zhi Yang, Wan-kang Zhang

Authors and Affiliations

  1. Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China

    Xue-zhi Yang, Wan-kang Zhang, Zi-qing Zhu, Wei Zhao, Ling-li Luo, Lu-ping Wang, Yan Chang & Wei Wei

  2. Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China

    Ying-jie Zhao

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Contributions

WW and XZY conceived and designed the experiments. XZY, WKZ, LPW, ZQZ, WZ, and LLL performed the experiments. XZY, WKZ, and LPW analyzed the data. WW, XZY, YC, and YJZ contributed reagents/materials/analysis tools. XZY wrote the manuscript.

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Correspondence to Xue-zhi Yang, Ying-jie Zhao, Yan Chang or Wei Wei.

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Yang, Xz., Zhang, Wk., Zhu, Zq. et al. GRK2-mediated phosphorylation and de-succinylation of PKM2 reduce macrophage glycolysis in rheumatoid arthritis. Acta Pharmacol Sin 46, 2693–2706 (2025). https://doi.org/10.1038/s41401-025-01582-y

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