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Excitatory amino acid transporters support mast cell degranulation via α-KG-mediated methylation of Spp1

Cellular & Molecular Immunology (2026)Cite this article

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Abstract

Excitatory amino acid transporters (EAATs) mediate the progression of inflammatory diseases. However, the involvement of EAATs in the activation of mast cells (MCs) and MC-associated diseases remains unclear. Here, we demonstrate that EAAT2 expression (encoded by Slc1a2) directed by immunoglobulin E (IgE)-mediated high-affinity IgE receptor (FcεRI)-p38 signaling is indispensable for MC degranulation through osteopontin (OPN, encoded by Spp1). Mechanistically, EAAT2 regulates intracellular glutamate/alpha-ketoglutarate/reactive oxygen species (ROS) metabolism to reduce the DNA and histone H3K9 methylation of Spp1. Most importantly, MC-specific depletion of Slc1a2 alleviates the allergic response in mice, and EAAT2 expression is positively correlated with MC-associated diseases in humans. Taken together, our findings establish a mechanistic link between amino acid transporters and epigenetic modifications with MC activation and provide potential therapeutic targets for allergic diseases.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (32521006, 32225047, and U22A20510), Yuelushan Laboratory Talent Program (2025RC3002), Double First-class Discipline Promotion Project (2023B10564001), Independent Research Fund of State Key Laboratory of Swine and Poultry Breeding Industry (2025ZQQZ-G26), Science and Technology Innovation Program of Hunan Province (2025RC4006), and Laboratory of Lingnan Modern Agriculture Project (NT2025004).

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  1. These authors contributed equally: Zhending Gan, Yaoyao Xia, Peng Bin.

Authors and Affiliations

  1. State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Laboratory of Lingnan Modern Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China

    Zhending Gan, Peng Bin, Muyang Zhao, Bingnan Liu & Wenkai Ren

  2. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China

    Zhending Gan

  3. College of Animal Science and Technology, Southwest University, Chongqing, China

    Yaoyao Xia

  4. Department of Dermatology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

    Youyou Zhou

  5. Yuelushan Laboratory, Changsha, China

    Wenkai Ren

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  1. Zhending Gan
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Contributions

W Ren designed the experiments. Z Gan, Y Xia, P Bin, M Zhao, and B Liu conducted the experiments. Y Xia and Y Zhou conducted the human experiments. Z Gan analyzed the data and drafted the manuscript. Y Xia, P Bin, and W Ren revised the manuscript. W Ren approved the final manuscript.

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Correspondence to Wenkai Ren.

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Gan, Z., Xia, Y., Bin, P. et al. Excitatory amino acid transporters support mast cell degranulation via α-KG-mediated methylation of Spp1. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-025-01375-7

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