Identification of Novel Targets for Treatment of Dilated Cardiomyopathy Based on the Ferroptosis and Immune Heterogeneity

Abstract

Purpose

This study aimed to investigate the role of ferroptosis in dilated cardiomyopathy (DCM) and to identify new targets for treatment and diagnosis of DCM.

Methods

GSE116250 and GSE145154 were downloaded from the Gene Expression Omnibus database. Unsupervised consensus clustering of DCM patients was used to confirm the impact of ferroptosis. Ferroptosis-related hub genes were identified by WGCNA and single cell sequencing analyses. Finally, we established a DCM mouse model via injection of Doxorubicin to verify the expression level of OTUD1 and colocalization between cell markers and OTUD1 in DCM mouse heart.

Results

A total of 13 ferroptosis-related differentially expressed genes (DEGs) were identified. The DCM patients were divided into two clusters according to the expression of 13 DEGs. The DCM patients in different clusters showed discrepancies in immune infiltration. Four hub genes were further identified by WGCNA analysis. Single cell data analysis revealed that OTUD1 may regulate B cells and DC cells and then participate in immune infiltration discrepancy. The upregulation of OTUD1 and the colocalization of OTUD1 with CD19 (B cell maker) and CD11c (DCs markers) markers were confirmed in DCM mouse hearts.

Conclusion

Ferroptosis and the immune microenvironment are closely associated with DCM, and OTUD1 may play an important role through B cells and DCs.

Keywords:

• dilated cardiomyopathy
• ferroptosis
• immune infiltrations
• single cell sequencing

Ethical Approval

The animal experiments were approved by the Animal Care and Use Committee of Guangdong Provincial People’s Hospital (No. KY-Q-2022-366-01). The experiment complied with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

Acknowledgments

We would like to thank the GEO (GSE116250, GSE145154) networks for providing the data.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by grants from Guangdong Provincial science and technology project (2020B1111170011); Guangdong Provincial science and technology project (KJ022021049); Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention (No.2017B030314041; Y0120220151). The work was not funded by any industry sponsors. The study sponsor/funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.