EV-Mediated Intracardiac Crosstalk Mitigates Doxorubicin-Induced Cardiotoxicity

Hongyun Wang; Yiqing Chen; Tianhui Wang; Xuan Ye; Xiao Zhang; Yuling Xie; Jinxin Xie; Qianwen Wu; Zilin Guo; Xiaoying Yang; Chang Liu; Lunan Wang; Guangpeng Li; Dongchao Lu; Priyanka Gokulnath; H Immo Lehmann; Guoping Li; Yuxiang Dai; Dragos Cretoiu; Joost P G Sluijter; Junjie Xiao

doi:10.1161/CIRCRESAHA.125.327827

EV-Mediated Intracardiac Crosstalk Mitigates Doxorubicin-Induced Cardiotoxicity

Circ Res. 2026 May 8;138(10):e327827. doi: 10.1161/CIRCRESAHA.125.327827. Epub 2026 Apr 8.

Authors

Hongyun Wang^#^{1

2}, Yiqing Chen^#³, Tianhui Wang^#^{1

2}, Xuan Ye^#², Xiao Zhang^{1

2}, Yuling Xie^{1

2}, Jinxin Xie^{1

2}, Qianwen Wu^{1

2}, Zilin Guo^{1

2}, Xiaoying Yang^{1

2}, Chang Liu², Lunan Wang², Guangpeng Li², Dongchao Lu⁴, Priyanka Gokulnath⁵, H Immo Lehmann⁵, Guoping Li⁵, Yuxiang Dai⁶, Dragos Cretoiu^{7

8}, Joost P G Sluijter^{9

10}, Junjie Xiao^{1

2}

Affiliations

¹ Cardiac Regeneration and Ageing Laboratory, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), and School of Life Science, Shanghai University, Nantong, China (H.W., T.W., X.Z., Y.X., J. Xie, Q.W., Z.G., X. Yang, J. Xiao).
² Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), Shanghai Engineering Research Center of Organ Repair, Institute of Cardiovascular Sciences, Shanghai University, China (H.W., T.W., X.Z., Y.X., J. Xie, Q.W., Z.G., X. Yang, C.L., L.W., Guangpeng Li, J. Xiao).
³ School of Traditional Chinese Medicine (Y.C., X. Ye), Shanghai University of Traditional Chinese Medicine, China.
⁴ School of Integrative Medicine (D.L.), Shanghai University of Traditional Chinese Medicine, China.
⁵ Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston (P.G., H.I.L., Guoping Li).
⁶ State Key Laboratory of Cardiovascular Diseases, NHC Laboratory of Ischemic Heart Diseases, Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, China (Y.D.).
⁷ Department of Medical Genetics, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania (D.C.).
⁸ Materno-Fetal Assistance Excellence Unit, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania (D.C.).
⁹ Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, the Netherlands (J.P.G.S.).
¹⁰ UMC Utrecht Regenerative Medicine Center, Circulatory Health Research Center, University Medical Center, Utrecht University, the Netherlands (J.P.G.S.).

^# Contributed equally.

PMID: 41948821
DOI: 10.1161/CIRCRESAHA.125.327827

Abstract

Background: Extracellular vesicles (EVs) are involved in exercise-induced cardiac protection. However, the effects and underlying mechanisms of tissue-specific molecular cargo packaged within these EVs, including PIWI (P-element induced wimpy testis)-interacting RNA (piRNA), remain poorly understood. In particular, the mechanistic contribution of exercised intracardiac EV-associated piRNAs to doxorubicin-induced cardiotoxicity (DCT) has not been defined.

Methods: Transgenic reporter mice and a cardiomyocyte-specific Rab27a (RAB27A, member RAS oncogene family) knockout strategy were used to investigate the contribution of cardiomyocyte-derived EVs to exercise-induced cardioprotection against DCT. To screen functionally relevant cardioprotective piRNA cargo, heart tissues from patients with dilated cardiomyopathy and experimental DCT models were analyzed, including cardiomyocyte-specific knockout mice, human embryonic stem cell-derived cardiomyocytes, and primary murine cardiomyocytes.

Results: We found that cardiomyocyte-derived EVs post-exercise were enriched for a cardiac-specific protective piRNA (piR-mmu-57256903), designated as an exercise-induced protective piRNA (EPPIR). EPPIR levels were significantly reduced in heart tissue from patients with dilated cardiomyopathy and DCT models. Functionally, EPPIR protects the heart against DCT by regulating KDM6B (lysine [K]-specific demethylase 6B)-H3K27me3 (trimethylated histone H3 at lysine 27)-Dtna epigenetic axis. In addition, EPPIR acts as a cardiomyocyte-specific suppressor of Tp53 (tumor protein p53).

Conclusions: We identify a previously unrecognized role for cardiomyocyte-derived EV-associated piRNA EPPIR in mediating exercise-induced cardioprotection. EPPIR exerts its protective effects through coordinated regulation of the KDM6B-Dtna axis and cardiomyocyte-specific suppressor of Tp53, providing mechanistic insight and highlighting a potential therapeutic strategy for DCT.

Keywords: doxorubicin; exercise; extracellular vesicles; heart failure; myocytes, cardiac.

MeSH terms

Animals
Cardiomyopathy, Dilated* / chemically induced
Cardiomyopathy, Dilated* / genetics
Cardiomyopathy, Dilated* / metabolism
Cardiomyopathy, Dilated* / pathology
Cardiotoxicity* / metabolism
Cardiotoxicity* / prevention & control
Cells, Cultured
Doxorubicin* / adverse effects
Doxorubicin* / toxicity
Extracellular Vesicles* / metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocytes, Cardiac* / drug effects
Myocytes, Cardiac* / metabolism
Myocytes, Cardiac* / pathology
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Doxorubicin
RNA, Small Interfering
Tumor Suppressor Protein p53
Trp53 protein, mouse