Targeting ERBB2 and PIK3R1 as a therapeutic strategy for dilated cardiomyopathy: A single-cell sequencing and mendelian randomization analysis.

BACKGROUND

Dilated cardiomyopathy (DCM) is widely recognized as a significant contributor to heart failure. Nevertheless, the absence of pharmaceutical interventions capable of reversing disease progression and improving prognosis underscores the imperative for additional research in this area.

METHODS

First, we identified and evaluated three gene sets, namely "SC-DCM", "EP-DCM" and "Drug", using big data and multiple bioinformatics analysis methods. Accordingly, drug-treatable ("Hub") genes in DCM were identified. Following this, four microarray expression profile datasets were employed to authenticate the expression levels and discriminatory efficacy of "Hub" genes. Additionally, mendelian randomization analysis was conducted to ascertain the causal association between the "Hub genes" and heart failure. Finally, the "DGIdb" was applied to identify "Hub" genes-targeted drugs. The "ssGSEA" algorithm assessed the level of immune cell infiltration in DCM.

RESULTS

Enrichment analysis showed that the "SC-DCM" and "EP-DCM" gene sets were closely associated with DCM. PIK3R1 and ERBB2 were identified as drug-treatable genes in DCM. Additional analysis using MR supported a causal relationship between ERBB2 and heart failure, but not PIK3R1. Moreover, PIK3R1 was positively correlated with immune activation, while ERBB2 was negatively correlated. We found that everolimus was a pharmacological inhibitor for both PIK3R1 and ERBB2. However, no pharmacological agonist was found for ERBB2.

CONCLUSION

PIK3R1 and ERBB2 are drug-treatable genes in DCM. ERBB2 has a causal effect on heart failure, and its normal expression may play a role in preventing the progression of DCM to heart failure. In addition, there is a cross-expression of PIK3R1 and ERBB2 genes in both DCM and tumors. The adaptive immune system and PIK3R1 may be involved in DCM disease progression, while ERBB2 exerts a protective effect against DCM.