Critical Role of the cGAS-STING Pathway in Doxorubicin-Induced Cardiotoxicity

Wei Luo; Xiaoyi Zou; Yidan Wang; Zheng Dong; Xinyu Weng; Zhiqiang Pei; Shuai Song; Yongchao Zhao; Zilun Wei; Rifeng Gao; Beijian Zhang; Liwei Liu; Peiyuan Bai; Jin Liu; Xiang Wang; Tingwen Gao; Yang Zhang; Xiaolei Sun; Hang Chen; Kai Hu; Shisuo Du; Aijun Sun; Junbo Ge

doi:10.1161/CIRCRESAHA.122.321587

Critical Role of the cGAS-STING Pathway in Doxorubicin-Induced Cardiotoxicity

Circ Res. 2023 May 26;132(11):e223-e242. doi: 10.1161/CIRCRESAHA.122.321587. Epub 2023 May 8.

Authors

Wei Luo^#^{1

2

3}, Xiaoyi Zou^#^{1

2

3}, Yidan Wang^#⁴, Zheng Dong^#^{1

2

3}, Xinyu Weng^{1

2

3}, Zhiqiang Pei^{1

2

3}, Shuai Song^{1

2

3}, Yongchao Zhao^{1

2

3}, Zilun Wei^{1

2

3}, Rifeng Gao⁵, Beijian Zhang^{1

2

3}, Liwei Liu^{1

2

3}, Peiyuan Bai^{1

2

3}, Jin Liu^{1

2

3}, Xiang Wang^{1

2

3}, Tingwen Gao^{1

2

3}, Yang Zhang⁶, Xiaolei Sun^{1

2

3}, Hang Chen^{1

2

3}, Kai Hu^{1

2

3}, Shisuo Du⁶, Aijun Sun^{1

2

3

7

8}, Junbo Ge^{1

2

3

7

8}

Affiliations

¹ Department 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.).
² Key Laboratory of Viral Heart Diseases, National Health Commission, 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.).
³ Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, 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.).
⁴ Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China (Y.W.).
⁵ Department of Cardiology, Shanghai Fifth People's Hospital (R.G.), Fudan University, Shanghai, China.
⁶ Department of Radiation Oncology, Zhongshan Hospital (Y.Z., S.D.), Fudan University, Shanghai, China.
⁷ National Clinical Research Center for Intervention Medicine, Shanghai, China (A.S., J.G.).
⁸ Institutes of Biomedical Sciences (A.S., J.G.), Fudan University, Shanghai, China.

^# Contributed equally.

PMID: 37154056
DOI: 10.1161/CIRCRESAHA.122.321587

Abstract

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 (Sting^flox/flox/Cdh5-Cre^ERT) 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.

Keywords: NAD; cardiotoxicity; doxorubicin; endothelial cells; mitochondria.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiotoxicity*
Doxorubicin / toxicity
Mice
NAD / metabolism
Nucleotidyltransferases / genetics
Nucleotidyltransferases / metabolism
Signal Transduction*

Substances

NAD
Nucleotidyltransferases
Doxorubicin