Related Experiment Video
Updated: Jul 31, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Critical Role of the cGAS-STING Pathway in Doxorubicin-Induced Cardiotoxicity
Wei Luo1,2,3, Xiaoyi Zou1,2,3, Yidan Wang4
1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (W.L., X.Z., Z.D., X.W., Z.P., S.S., Y.Z., Z.W., B.Z., L.L., P.B., J.L., X.W., T.G., X.S., H.C., K.H., A.S., J.G.).
Background:
Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING (stimulator of interferon genes) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC).
Methods:
Mice were treated with low-dose doxorubicin to induce chronic DIC. The role of the cGAS-STING pathway in DIC was evaluated in cGAS-deficiency (cGAS-/-), Sting-deficiency (Sting-/-), and interferon regulatory factor 3 (Irf3)-deficiency (Irf3-/-) mice. Endothelial cell (EC)-specific conditional Sting deficiency (Stingflox/flox/Cdh5-CreERT) mice were used to assess the importance of this pathway in ECs during DIC. We also examined the direct effects of the cGAS-STING pathway on nicotinamide adenine dinucleotide (NAD) homeostasis in vitro and in vivo.
Results:
In the chronic DIC model, we observed significant activation of the cGAS-STING pathway in cardiac ECs. Global cGAS, Sting, and Irf3 deficiency all markedly ameliorated DIC. EC-specific Sting deficiency significantly prevented DIC and endothelial dysfunction. Mechanistically, doxorubicin activated the cardiac EC cGAS-STING pathway and its target, IRF3, which directly induced CD38 expression. In cardiac ECs, the cGAS-STING pathway caused a reduction in NAD levels and subsequent mitochondrial dysfunction via the intracellular NAD glycohydrolase (NADase) activity of CD38. Furthermore, the cardiac EC cGAS-STING pathway also regulates NAD homeostasis and mitochondrial bioenergetics in cardiomyocytes through the ecto-NADase activity of CD38. We also demonstrated that pharmacological inhibition of TANK-binding kinase 1 or CD38 effectively ameliorated DIC without compromising the anticancer effects of doxorubicin.
Conclusions:
Our findings indicate a critical role of the cardiac EC cGAS-STING pathway in DIC. The cGAS-STING pathway may represent a novel therapeutic target for preventing DIC.
Insights
Doxorubicin-induced cardiotoxicity is mediated by the cGAS-STING pathway in cardiac endothelial cells. Inhibiting this pathway or CD38 may prevent heart damage without affecting chemotherapy efficacy.
Area of Science:
- Cardiovascular Research
- Oncology
- Immunology
Background:
- Doxorubicin is a vital chemotherapy agent but causes severe cardiotoxicity.
- The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING pathway is implicated in cardiovascular damage.
- This study investigates the cGAS-STING pathway's role in doxorubicin-induced cardiotoxicity (DIC).
Purpose of the Study:
- To elucidate the mechanism of doxorubicin-induced cardiotoxicity (DIC).
- To determine the role of the cGAS-STING pathway in cardiac endothelial cells (CECs) during DIC.
- To explore potential therapeutic targets for mitigating DIC.
Main Methods:
- Utilized a chronic DIC mouse model with low-dose doxorubicin.
- Assessed DIC in mice deficient in cGAS, STING, or IRF3.
- Examined endothelial cell-specific STING deficiency and its impact on DIC.
- Investigated the cGAS-STING pathway's effect on nicotinamide adenine dinucleotide (NAD) homeostasis in vitro and in vivo.
Main Results:
- Significant cGAS-STING pathway activation was observed in cardiac ECs during chronic DIC.
- Deficiency in cGAS, STING, or IRF3 markedly reduced DIC.
- Endothelial cell-specific STING deficiency prevented DIC and endothelial dysfunction.
- Doxorubicin-induced cGAS-STING activation led to CD38 upregulation, reducing NAD levels and causing mitochondrial dysfunction.
- Pharmacological inhibition of TBK1 or CD38 ameliorated DIC without compromising doxorubicin's anti-cancer effects.
Conclusions:
- The cardiac endothelial cell cGAS-STING pathway plays a crucial role in doxorubicin-induced cardiotoxicity.
- Targeting the cGAS-STING pathway or CD38 presents a promising therapeutic strategy for preventing DIC.
Related Concept Videos
01:26Heart Failure Drugs: Inotropic Agents
01:09GPCRs Regulate Adenylyl Cylase Activity
01:25Antianginal Drugs: Calcium Channel Blockers and Ranolazine
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...
01:21G-Protein Gated Ion Channels
Sensory...
01:30Cardiomyopathy II: Dilated Cardiomyopathy
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System