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Peer-reviewedCC BYFrontiers in Physiology

Metabolic reprogramming of CCR2+ MHC IIhigh macrophage contributes to myocarditis induced by Doxorubicin

  • Yingxin Li1
  • Yingxin Li2
  • Yingxin Li3
  • Huiwen Jiang4
  • Jiawei Shi1
  • Jiawei Shi2
  • Jiawei Shi3
  • Jiani Qiu1
  • Jiani Qiu2
  • Jiani Qiu3
  • Junmin Zhang1
  • Junmin Zhang2
29 more authors
  • Junmin Zhang3
  • Jing Liu1
  • Jing Liu2
  • Jing Liu3
  • Yilan Zhou1
  • Yilan Zhou2
  • Yilan Zhou3
  • Ying Bai1
  • Ying Bai2
  • Ying Bai3
  • Jingrong Jiang1
  • Jingrong Jiang2
  • Jingrong Jiang3
  • Qiaofeng Jin1
  • Qiaofeng Jin2
  • Qiaofeng Jin3
  • Li Zhang1
  • Li Zhang2
  • Li Zhang3
  • Haotian Gu5
  • Mingxing Xie1
  • Mingxing Xie2
  • Mingxing Xie3
  • Tianshu Liu1
  • Tianshu Liu2
  • Tianshu Liu3
  • Jing Wang1
  • Jing Wang2
  • Jing Wang3
5 affiliations
  1. 1Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  2. 2Hubei Province Clinical Research Center for Medical Imaging, Wuhan, China
  3. 3Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
  4. 4Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  5. 5School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London BHF Centre of Research Excellence, London, United Kingdom
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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.

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Cite

BibTeXRIS
BibTeX
@article{li2026metabolic,
  title = {{Metabolic reprogramming of CCR2+ MHC IIhigh macrophage contributes to myocarditis induced by Doxorubicin}},
  author = {Yingxin Li and Yingxin Li and Yingxin Li and Huiwen Jiang and Jiawei Shi and Jiawei Shi and Jiawei Shi and Jiani Qiu and Jiani Qiu and Jiani Qiu and Junmin Zhang and Junmin Zhang and Junmin Zhang and Jing Liu and Jing Liu and Jing Liu and Yilan Zhou and Yilan Zhou and Yilan Zhou and Ying Bai and Ying Bai and Ying Bai and Jingrong Jiang and Jingrong Jiang and Jingrong Jiang and Qiaofeng Jin and Qiaofeng Jin and Qiaofeng Jin and Li Zhang and Li Zhang and Li Zhang and Haotian Gu and Mingxing Xie and Mingxing Xie and Mingxing Xie and Tianshu Liu and Tianshu Liu and Tianshu Liu and Jing Wang and Jing Wang and Jing Wang},
  journal = {Frontiers in Physiology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphys.2026.1883296},
  url = {https://doi.org/10.3389/fphys.2026.1883296},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Metabolic reprogramming of CCR2+ MHC IIhigh macrophage contributes to myocarditis induced by Doxorubicin
AU  - Yingxin Li
AU  - Yingxin Li
AU  - Yingxin Li
AU  - Huiwen Jiang
AU  - Jiawei Shi
AU  - Jiawei Shi
AU  - Jiawei Shi
AU  - Jiani Qiu
AU  - Jiani Qiu
AU  - Jiani Qiu
AU  - Junmin Zhang
AU  - Junmin Zhang
AU  - Junmin Zhang
AU  - Jing Liu
AU  - Jing Liu
AU  - Jing Liu
AU  - Yilan Zhou
AU  - Yilan Zhou
AU  - Yilan Zhou
AU  - Ying Bai
AU  - Ying Bai
AU  - Ying Bai
AU  - Jingrong Jiang
AU  - Jingrong Jiang
AU  - Jingrong Jiang
AU  - Qiaofeng Jin
AU  - Qiaofeng Jin
AU  - Qiaofeng Jin
AU  - Li Zhang
AU  - Li Zhang
AU  - Li Zhang
AU  - Haotian Gu
AU  - Mingxing Xie
AU  - Mingxing Xie
AU  - Mingxing Xie
AU  - Tianshu Liu
AU  - Tianshu Liu
AU  - Tianshu Liu
AU  - Jing Wang
AU  - Jing Wang
AU  - Jing Wang
PY  - 2026
DA  - 2026/10/27
JO  - Frontiers in Physiology
DO  - 10.3389/fphys.2026.1883296
UR  - https://doi.org/10.3389/fphys.2026.1883296
AB  - 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.
SN  - 1664-042X
ER  -