{
  "abstract": "BackgroundDoxorubicin-induced cardiotoxicity remains a major clinical challenge. The intricate immunomodulatory pathways responsible for cardiac damage remain incompletely defined. Cardiac CCR2+ MHC IIhigh macrophages have emerged as a critical subset contributing to inflammatory cardiovascular injury. However, the precise exacerbating role and mechanisms by which these macrophages contribute to doxorubicin-induced myocardial injury remain elusive. Metabolic reprogramming significantly influences the transition of macrophages to an inflammatory phenotype, and pyruvate kinase M2 (PKM2), a key rate-limiting enzyme of glucose metabolism, may be a possible regulatory node and a promising therapeutic target for intervention.MethodsDoxorubicin-induced cardiotoxicity model was established in C57BL6/J mice. This model was utilized to assess the dynamic change relationship between cardiac function, cardiac CCR2+ MHC IIhigh macrophages, and myocardial injury remodeling. Also, the crosstalk between macrophage phenotypic switching and cardiomyocyte damage was explored in vitro. We further investigated the role of PKM2 in CCR2+ macrophage metabolic reprogramming and the therapeutic potential of using Shikonin to inhibit PKM2 to ameliorate cardiac injury. Moreover, peripheral blood cells from patients receiving Doxorubicin chemotherapy were used to verify the changes in PKM2 in macrophages, which revealed the role of metabolic reprogramming in pro-inflammatory macrophages.ResultsCCR2+ MHC IIhigh macrophages may play a crucial role in exacerbating sustained cardiotoxicity caused by Doxorubicin. In vitro studies have shown that PKM2 facilitates the transition of macrophages into a pro-inflammatory CCR2+ phenotype. The phosphorylation of PKM2 mechanistically contributes to the metabolic reprogramming of these pro-inflammatory CCR2+ macrophages. In vivo and in vitro experiments have demonstrated that pharmacological inhibition of PKM2 with Shikonin mitigates doxorubicin-induced cardiotoxicity.ConclusionOur results reveal a pivotal metabolic regulator of cardiac CCR2+ MHC IIhigh macrophages through metabolic reprogramming. Targeting PKM2 could offer a novel approach for mitigating Doxorubicin-induced myocardial inflammatory damage. Exploring the impact of CCR2+ macrophages on exacerbating myocardial injury sheds new light on the interplay between aberrant immune response of macrophage and Doxorubicin-induced myocarditis.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China",
    "Hubei Province Clinical Research Center for Medical Imaging, Wuhan, China",
    "Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China",
    "Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China",
    "School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London BHF Centre of Research Excellence, London, United Kingdom"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 41,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yingxin Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Yingxin Li"
    },
    {
      "affs": [
        2
      ],
      "name": "Yingxin Li"
    },
    {
      "affs": [
        3
      ],
      "name": "Huiwen Jiang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiawei Shi"
    },
    {
      "affs": [
        1
      ],
      "name": "Jiawei Shi"
    },
    {
      "affs": [
        2
      ],
      "name": "Jiawei Shi"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiani Qiu"
    },
    {
      "affs": [
        1
      ],
      "name": "Jiani Qiu"
    },
    {
      "affs": [
        2
      ],
      "name": "Jiani Qiu"
    },
    {
      "affs": [
        0
      ],
      "name": "Junmin Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Junmin Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Junmin Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jing Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Jing Liu"
    },
    {
      "affs": [
        2
      ],
      "name": "Jing Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yilan Zhou"
    },
    {
      "affs": [
        1
      ],
      "name": "Yilan Zhou"
    },
    {
      "affs": [
        2
      ],
      "name": "Yilan Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Ying Bai"
    },
    {
      "affs": [
        1
      ],
      "name": "Ying Bai"
    },
    {
      "affs": [
        2
      ],
      "name": "Ying Bai"
    },
    {
      "affs": [
        0
      ],
      "name": "Jingrong Jiang"
    },
    {
      "affs": [
        1
      ],
      "name": "Jingrong Jiang"
    },
    {
      "affs": [
        2
      ],
      "name": "Jingrong Jiang"
    },
    {
      "affs": [
        0
      ],
      "name": "Qiaofeng Jin"
    },
    {
      "affs": [
        1
      ],
      "name": "Qiaofeng Jin"
    },
    {
      "affs": [
        2
      ],
      "name": "Qiaofeng Jin"
    },
    {
      "affs": [
        0
      ],
      "name": "Li Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Li Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Li Zhang"
    },
    {
      "affs": [
        4
      ],
      "name": "Haotian Gu"
    },
    {
      "affs": [
        0
      ],
      "name": "Mingxing Xie"
    },
    {
      "affs": [
        1
      ],
      "name": "Mingxing Xie"
    },
    {
      "affs": [
        2
      ],
      "name": "Mingxing Xie"
    },
    {
      "affs": [
        0
      ],
      "name": "Tianshu Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Tianshu Liu"
    },
    {
      "affs": [
        2
      ],
      "name": "Tianshu Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Jing Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Jing Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Jing Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/25k35wvnqgn05.bib",
  "cited_by": 0,
  "doi": "10.3389/fphys.2026.1883296",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fphys.2026.1883296/full",
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  "landing_url": "https://doi.org/10.3389/fphys.2026.1883296",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
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  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
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  "pdf_url": "https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2026.1883296/pdf",
  "pmcid": null,
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  "published": "2026-10-27",
  "publisher": "Frontiers Media S.A.",
  "ris": "https://research.draconitic.com/paper/25k35wvnqgn05.ris",
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    {
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  "title": "Metabolic reprogramming of CCR2+ MHC IIhigh macrophage contributes to myocarditis induced by Doxorubicin",
  "title_text": "Metabolic reprogramming of CCR2+ MHC IIhigh macrophage contributes to myocarditis induced by Doxorubicin",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T14:21:48Z",
  "url": "https://research.draconitic.com/paper/25k35wvnqgn05",
  "venue": "Frontiers in Physiology",
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