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A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Leonurine Ameliorates Doxorubicin-Induced Cardiotoxicity via STING/NF-κB/NLRP3 Inflammasome Signaling Pathway
Wang Jun1,2,3,4, Chen Xiaoyang5,6,7, Xu Jianglin2,3,4,8
1School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
Abstract:
Doxorubicin-induced cardiomyopathy (DIC) remains a dose-limiting clinical challenge. This study reveals that cardiac vascular endothelial cells (CVECs) act as initial sensors of doxorubicin cardiotoxicity: circulating doxorubicin activates the cGAS‑STING pathway in CVECs, triggering NLRP3 inflammasome‑mediated pyroptosis and release of pathogenic extracellular vesicles that induce mitochondrial dysfunction in neighboring cardiomyocytes, establishing a self‑perpetuating injury loop. Leonurine (LEO), a natural alkaloid, is identified as a direct STING inhibitor that specifically binds the TYR261 residue, blocking both STING oligomerization and STING‑TBK1 heterodimer formation-a mechanism distinct from known STING inhibitors. LEO exerts hierarchical dual protection: directly preserving cardiomyocyte mitochondria while primarily inhibiting endothelial STING to disrupt the pathogenic loop. This endothelial‑centric strategy shifts the therapeutic paradigm from direct cardiomyocyte protection to upstream endothelial intervention, establishing LEO as a promising candidate for DIC.
Insights
Doxorubicin cardiotoxicity is initiated by cardiac endothelial cells activating the cGAS-STING pathway. Leonurine (LEO) inhibits this pathway, offering dual protection against doxorubicin-induced cardiomyopathy (DIC).
Area of Science:
- Cardiovascular Biology
- Molecular Toxicology
- Pharmacology
Background:
- Doxorubicin-induced cardiomyopathy (DIC) is a significant dose-limiting side effect of chemotherapy.
- Cardiac vascular endothelial cells (CVECs) are implicated as early responders to doxorubicin cardiotoxicity.
Purpose of the Study:
- To elucidate the initial cellular mechanisms of doxorubicin cardiotoxicity.
- To identify therapeutic strategies targeting the early stages of DIC.
- To investigate the protective effects of Leonurine (LEO) against DIC.
Main Methods:
- Investigated the role of the cGAS-STING and NLRP3 inflammasome pathways in CVECs following doxorubicin exposure.
- Utilized Leonurine (LEO) as a STING inhibitor to assess its therapeutic potential.
- Examined the effects of LEO on endothelial cells, cardiomyocytes, and mitochondrial function in vitro and in vivo models of DIC.
Main Results:
- Doxorubicin activates the cGAS-STING pathway in CVECs, leading to NLRP3 inflammasome activation, pyroptosis, and release of pathogenic extracellular vesicles.
- These vesicles induce mitochondrial dysfunction in adjacent cardiomyocytes, creating a self-perpetuating injury loop.
- Leonurine (LEO), a natural alkaloid, directly inhibits STING by binding TYR261, preventing STING oligomerization and STING-TBK1 complex formation.
- LEO demonstrated dual protective effects by preserving cardiomyocyte mitochondria and inhibiting endothelial STING activation.
Conclusions:
- CVECs are critical initiators of doxorubicin cardiotoxicity via the cGAS-STING-NLRP3 inflammasome axis.
- Leonurine (LEO) represents a novel therapeutic agent for DIC by targeting endothelial STING.
- This endothelial-centric approach offers a new paradigm for preventing and treating doxorubicin-induced cardiac damage.
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