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Journal of Advanced Research

Journal of Advanced Research

IF: 11.4
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Pleiotropic role of CCR9/CCL25 signaling in adriamycin-induced cardiomyopathy

Published:1 September 2025 DOI: 10.1016/j.jare.2024.10.018
Xue Wu , Zheng Wang , Zhenxing Liang , Ning Li , Junmin Chen , Qiong Liu , Wangrui Lei , Xiaopeng Wu , Chenxi Lu , Chao Deng , Ying Chen , Xue Wang , Jinhong Wei , Yang Yang

Abstract

Introduction

Adriamycin (ADR)-induced cardiomyopathy is a common problem in many cancer survivors. Recently, specific chemokine receptors have garnered interest as therapeutic targets in cardiovascular diseases.

Objectives

This study aim to report the role of C–C chemokine receptor 9 (CCR9)/C–C chemokine ligand 25 (CCL25) and its therapeutic potential in ADR-induced cardiomyopathy.

Methods

Functional gene knockout and overexpression mouse models were utilized to investigate the role of CCR9 against ADR-induced cardiomyopathy. Transcriptome sequencing was also performed to identify the downstream molecular mechanisms of CCR9.

Results

This study revealed that CCR9 and CCL25 levels were increased in mice and HL-1 cells injured by ADR, consistent with the results of patients with heart failure. Both in vivo and in vitro, CCR9 overexpression overtly aggravated cardiac dysfunction, accompanied by decreased AMPK activity and increased mitochondrial dysfunction, fibrosis, oxidative stress, and apoptosis. However, the cardiac harmful effects of ADR were reserved by CCR9 knockdown, as well as CCR9 overexpression aggravated cardiotoxicity were reserved by AMPK agonist GSK621. By constructing different domain-missing CCR9 mutants, we suspected that the △4 region of CCR9 is important for AMPK activity. Furthermore, transcriptome sequencing? further illustrated the mechanism of CCR9 overexpression aggravated ADR-induced cardiotoxicity, which was associated with CYP1A1. Finally, lithospermic acid (LA) was screened and alleviated ADR-induced cardiotoxicity through regulation of CCR9/CCL25-AMPK signaling, bolstering CCR9-targeted potential clinical application.

Conclusion

These findings present a promising target and drug for treating chemotherapy-induced cardiotoxicity.

Substances (66)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Fluconazole 86386-73-4 C13H12F2N6O 1188 suppliers $5.00-$1504.50
Fluconazole 86386-73-4 C13H12F2N6O 1188 suppliers $5.00-$1504.50
Fluconazole 86386-73-4 C13H12F2N6O 1188 suppliers $5.00-$1504.50
Fluconazole 86386-73-4 C13H12F2N6O 1188 suppliers $5.00-$1504.50
5-Fluorocytosine 2022-85-7 C4H4FN3O 942 suppliers $3.00-$1500.00
5-Fluorocytosine 2022-85-7 C4H4FN3O 942 suppliers $3.00-$1500.00
5-Fluorocytosine 2022-85-7 C4H4FN3O 942 suppliers $3.00-$1500.00
5-Fluorocytosine 2022-85-7 C4H4FN3O 942 suppliers $3.00-$1500.00
Itraconazole 84625-61-6 C35H38Cl2N8O4 881 suppliers $4.00-$1504.50
Itraconazole 84625-61-6 C35H38Cl2N8O4 881 suppliers $4.00-$1504.50

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