Naringenin exerts antiarrhythmic action in septic cardiomyopathy by downregulating the CaMKⅡ/Drp1/Bcl-2 pathway

Yali Zhang; Yu Zhang; Hongmei Deng; Qishu Zeng; Zhu Zhu; Zhaolun Zhang; Chunyu Zhang; Minghao Li; Jianhong Li; Guang Li; Jian Feng

doi:10.1016/j.phymed.2025.157006

Naringenin exerts antiarrhythmic action in septic cardiomyopathy by downregulating the CaMKⅡ/Drp1/Bcl-2 pathway

Phytomedicine. 2025 Jun 20:145:157006. doi: 10.1016/j.phymed.2025.157006. Online ahead of print.

Authors

Yali Zhang¹, Yu Zhang², Hongmei Deng², Qishu Zeng³, Zhu Zhu⁴, Zhaolun Zhang¹, Chunyu Zhang¹, Minghao Li¹, Jianhong Li⁵, Guang Li⁶, Jian Feng⁷

Affiliations

¹ Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China.
² Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
³ Department of Emergency, The People's Hospital of Jianyang City, Chengdu, Sichuan, China.
⁴ Department of Pathology, Yan'an University Xianyang Hospital, Xianyang, Shaanxi, China.
⁵ Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China; Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
⁶ Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: liguang@swmu.edu.cn.
⁷ Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China. Electronic address: jerryfeng@swmu.edu.cn.

PMID: 40602293
DOI: 10.1016/j.phymed.2025.157006

Abstract

Background: Septic cardiomyopathy (SCM) is associated with sepsis and is often accompanied by progressive arrhythmia. Naringenin (Nar) is a natural dihydroflavonoid compound that plays a protective role in various cardiovascular diseases. Calcium/calmodulin-dependent kinase II (CaMKII) is a key therapeutic target in cardiac arrhythmias.

Purpose: This study investigated the effect of naringenin on arrhythmia and cardiac electrophysiology in SCM and explored the mechanism involved.

Methods: Lipopolysaccharide was used to establish SCM in a mouse model and in an H9c2 cell line. The protective role of naringenin in SCM was investigated by pretreatment with naringenin, amiodarone, and a CaMKII inhibitor (KN-93). Cardiac function, susceptibility to arrhythmia, and electrophysiological changes were assessed in the mice using echocardiography, electrocardiography, and optical mapping techniques. Network pharmacology approaches, molecular docking, and molecular dynamics simulations were used to screen for pivotal targets. The mechanism(s) underlying the protective impact of naringenin on SCM were examined in vivo, ex vivo, and in vitro.

Results: Naringenin protected against SCM by exerting anti-inflammatory effects, alleviating myocardial injury, improving cardiac dysfunction, reducing the susceptibility to arrhythmia, and stabilizing electrophysiology. Network pharmacology, molecular docking, and molecular dynamics simulations indicated that the key target protein of naringenin may be Bcl-2. Further studies confirmed that naringenin attenuated apoptosis, improved mitochondrial dysfunction, and downregulated the CaMKⅡ/Drp1/Bcl-2 pathway in SCM.

Conclusions: Naringenin attenuates the phosphorylation of Drp1 by inhibiting phosphorylation of CaMKⅡ, thereby ameliorating mitochondrial dysfunction, suppressing apoptosis, modulating myocardial electrophysiology, and ultimately reducing susceptibility to arrhythmia while improving cardiac function in SCM.

Keywords: Arrhythmia; Cardiac electrophysiology; Naringenin; Septic cardiomyopathy.