Role of mitochondrial metabolism in immune checkpoint inhibitors-related myocarditis

Xin Zhang; Yi Gan; Haoshuai Zhu; Zhihao Liu; Xiaojing Yao; Chao Cheng; Zhenguo Liu; Chunhua Su; Jianyong Zou

doi:10.3389/fcvm.2023.1112222

Role of mitochondrial metabolism in immune checkpoint inhibitors-related myocarditis

Front Cardiovasc Med. 2023 Jan 24:10:1112222. doi: 10.3389/fcvm.2023.1112222. eCollection 2023.

Authors

Xin Zhang¹, Yi Gan¹, Haoshuai Zhu¹, Zhihao Liu¹, Xiaojing Yao¹, Chao Cheng¹, Zhenguo Liu¹, Chunhua Su¹, Jianyong Zou¹

Affiliation

¹ Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Abstract

Background: Immune checkpoint inhibitor-related myocarditis is the deadliest complication of immunotherapy. However, the underlying pathophysiological mechanisms of its occurrence and development remain unclear. Due to the long-term lack of effective early diagnosis and treatment options, it is of great significance to understand the pathophysiological mechanism of immune checkpoint inhibitor-related myocarditis.

Methods: Tissue samples from three patients with immune checkpoint inhibitor-related myocarditis and three control tissue samples were collected for protein analysis. Differentially expressed proteins were screened out using quantitative proteomics technology based on TMT markers. Protein-protein interaction (PPI) and Gene Ontology (GO) functional enrichment analyses of cross-factors were subsequently performed. Combined with the PD-L1 subcellular organelle- level protein interaction network, we searched for hub proteins involved in immune checkpoint inhibitor-related myocarditis and explored potential drug sensitivity and disease correlation.

Results: A total of 306 differentially expressed proteins were identified in immune checkpoint inhibitor-related myocarditis. Enrichment analysis showed that the differentially expressed proteins were closely related to mitochondrial metabolism. By analyzing mitochondria-related proteins and PD-L1-related proteins, we found four hub proteins, mammalian target of rapamycin (mTOR), Glycogen synthase kinase 3β (GSK3β), Protein tyrosine phosphatase non-receptor type 11 (PTPN11), and Mitofusin 2 (MFN2), indicating that they are closely related to immune checkpoint inhibitor-related myocarditis. Finally, we explored potential drugs for the treatment of immune checkpoint inhibitor-related myocarditis.

Conclusion: Mitochondrial metabolism is involved in the process of immune checkpoint inhibitor-related myocarditis, and we identified four hub proteins, which may become new biomarkers for the early diagnosis and treatment of immune checkpoint inhibitor-related myocarditis.

Keywords: immune checkpoint inhibitors; immunity therapy; mitochondrial metabolism; myocarditis; proteomics.

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 82001331).