Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice PMID: 40456736

ADC Targets in Oncology

2026-04-10

Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice

Nat Commun. 2025 Jun 2;16(1):5101. doi: 10.1038/s41467-025-60123-7.

Zhenyu Kang ^# ¹ , Mengling Yang ^# ¹ , Yue Liu ^# ² , Yang Gui ¹ , Yalan Dong ¹ , Haifeng Zhou ¹ , Zili Zhang ¹ , Mingyue Li ³ , Heng Fan ¹ , Zheng Li ¹ , Junjie Lu ⁴ , Junyi Li ¹ , Rui Zhu ¹ , Chengyu Yin ¹ , Boyi Liu ⁵ , Feng Jiang ⁶ , Kun Huang ⁷ , Alexey Sarapultsev ⁸ , Fangfei Li ⁹ , Ge Zhang ¹⁰ , Ling Zhao ¹¹ , Yanyi Wang ¹² , Yunjia Ning ¹² ¹³ , Xiang Cheng ¹⁴ ¹⁵ , Sarajo K Mohanta ¹⁶ ¹⁷ ¹⁸ , Changjun Yin ¹⁶ ¹⁸ ¹⁹ ²⁰ , Shanshan Luo ²¹ , Andreas J R Habenicht ²² ²³ ²⁴ ²⁵ , Desheng Hu ²⁶ ²⁷ ²⁸

Affiliations

1. Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2. Cardiovascular Disease Center, Xiyuan Hospital of China academy of Chinese Medical Sciences, Beijing, China.
3. Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing, China.
4. Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei Province, Xiangyang, China.
5. Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310000, China.
6. College of International Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
7. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
8. Russian-Chinese Education and Research Center of System Pathology, South Ural State University, Chelyabinsk, Russia.
9. Shum Yiu Foon Sum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
10. Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
11. State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.
12. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
13. Hubei Jiangxia Laboratory, Wuhan, China.
14. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
15. Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
16. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany.
17. German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
18. Easemedcontrol R & D; Schraudolphstraße 5, Munich, Germany.
19. Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
20. Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
21. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
22. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany. [email protected].
23. German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany. [email protected].
24. Easemedcontrol R & D; Schraudolphstraße 5, Munich, Germany. [email protected].
25. Department of Cardiology, the Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Gulou, Nanjing, Jiangsu, China. [email protected].
26. Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
27. Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
28. China-Russia Medical Research Center for Stress Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
# Contributed equally.

Abstract

Myocardial ischemia-reperfusion injury (MIRI) is a life-threatening complication of myocardial infarcts, with inner mitochondrial membrane protein dysfunction involved in MIRI-induced heart injury. The role of outer mitochondrial membrane protein mitochondrial Antiviral signaling protein (MAVS) is unknown. Here, we show that MAVS expression increases in infarcted myocardium of male wild-type mice. Global MAVS-knock-out or myocardial-specific MAVS knockdown protects male mice from acute and chronic MIRI. MIRI induces double-stranded RNA in affected myocardium, activating intracellular retinoic acid-inducible gene I (RIG-I) signaling, which leads to MAVS aggregation and subsequent non-canonical downstream signaling. MAVS aggregates recruit tumor necrosis factor-associated factor family 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), the activating mitogen-activated protein kinase (MAPK) pathway and Apoptosis. MAVS-knock-out reduces c-jun-NH2 terminal kinase (JNK) phosphorylation and Apoptosis. JNK inhibition protects against MIRI in wild-type male mice, whereas JNK agonist impairs protection in MAVS-knock-out male mice. MIRI activates RIG-I/MAVS pathway and subsequently triggers the TAK1/TRAF6 complex, leading to the activation of the MAPK/JNK signaling cascade. This sequential activation cascade may serve as a potential therapeutic target for MIRI.