2. Academic Validation
  3. ELABELA-32 Alleviates Doxorubicin-Induced Chronic Cardiotoxicity by Inhibiting the TGF-β/Smad Signaling Pathway

ELABELA-32 Alleviates Doxorubicin-Induced Chronic Cardiotoxicity by Inhibiting the TGF-β/Smad Signaling Pathway

  • Cardiovasc Toxicol. 2025 Jul;25(7):1009-1021. doi: 10.1007/s12012-025-10010-w.
Shuang Zhou 1,  Zhuo Meng 2,  Lin Lu 1,  Junhao Xie 1,  Lihua Li 1,  Huilong Cheng 1,  Kun Sun 3,  Juxiang Wang 4
Affiliations

Affiliations

  • 1 Department of Intensive Care Unit, Xiamen Cardiovascular Hospital, Xiamen University, No. 2999, Jinshan Road, Huli District, Xiamen, Fujian, China.
  • 2 Department of Pediatric Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kongjiang Road, Yangpu District, Shanghai, China. sunkun@xinhuamed.com.cn.
  • 4 Department of Intensive Care Unit, Xiamen Cardiovascular Hospital, Xiamen University, No. 2999, Jinshan Road, Huli District, Xiamen, Fujian, China. xmwjx2012@xmu.edu.cn.
PMID: 40389799 DOI: 10.1007/s12012-025-10010-w
Abstract

Cardiac fibrosis, oxidative stress, and cardiomyocyte Apoptosis are key contributors to the progression of doxorubicin (DOX)-induced cardiotoxicity. ELABELA (ELA) is an early endogenous ligand of apelin receptor (APJ/APLNR), which is a G protein-coupled receptor with seven transmembrane domains. Our present study aimed to investigate the protective role and underlying mechanism of ELA-32 in mitigating oxidative stress and fibrosis associated with DOX-induced cardiotoxicity. Using a mouse model of chronic DOX cardiotoxicity (5 mg/kg, i.p, once a week for four times, the total cumulative dose is 20 mg/kg), it was found that exogenous administration of ELA-32 using a microinjection pump significantly improved cardiac function, reduced oxidative stress, and myocardial fibrosis, and enhanced survival. Furthermore, pretreatment with ELA-32 peptide protected rat cardiomyocytes (H9C2 cells) from DOX-induced cytotoxicity in vitro. However, these cardioprotective effects of ELA-32 were no longer observed after activation of the Smad signaling pathway using TGF-β1. In summary, ELA-32 attenuated DOX-induced cardiac fibrosis through by modulating the TGF-β/Smad signaling pathway, thus highlighting its potential as a therapeutic agent for preventing chronic DOX-related cardiotoxicity.

Keywords

APJ; Cardio-protective effect; Doxorubicin; ELABELA; Smad.

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