Yuanting Zhu,1,* Qiang Zhang,2,* Yanbo Wang,1,* Wenqiang Liu,3 Shichen Zeng,4 Qinghua Yuan,1 Kun Zhang1 

1Department of Cardiology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of China; 2Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 3Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China; 4Clinical Medicine, Changsha Medical University, Changsha, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Kun Zhang; Qinghua Yuan, Department of Cardiology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of China, Email zhangk65@mail.sysu.edu.cn; yuanqinghua@sysush.com

Purpose: Heart failure (HF) remains a leading cause of mortality and morbidity in cardiovascular disease. Research has shown that necroptosis contributes to HF, and immune infiltration has been reported to be implicated in HF. However, the specific mechanisms by which necroptosis and immune infiltration promote HF remain poorly understood. This study aims to elucidate these mechanisms, thereby providing new insights for future therapeutic strategies.
Methods and Results: In the GSE21610 dataset, there were 1848 differentially expressed genes (DEGs), 14 of which related to necroptosis (NRDEGs) in HF. Gene Set Enrichment Analysis (GSEA) indicated that Th1 and Th2 cell differentiation, TGF-beta signaling, Renin secretion, and Wnt signaling pathways may be closely associated with HF. The NRDEGs may play a role in responding to mechanical stimuli, membrane rafts, cytokine receptor binding, or the necroptosis signaling pathway. The protein-protein interaction (PPI) network identified EGFR, TXN, FASLG, MAPK14, and CASP8 as hub NRDEGs. Furthermore, immune infiltration analysis of CIBERSORT algorithm suggested that M2 macrophages, memory B cells, monocytes, regulatory T cells (Tregs), follicular helper T cells, and gamma delta T cells may participate in the development of HF. The hub NRDEGs, including EGFR, FASLG, and TXN, exhibited significant correlations with various immune cell types. Finally, animal models confirmed that in the HF group, EGFR and FASLG were up-regulated, while TXN was down-regulated.
Conclusion: The present findings demonstrate that necroptosis and immune infiltration are associated with the development of HF. This study provides valuable insights and recommendations for the clinical management of HF.

Keywords: heart failure, differentially expressed genes, necroptosis, immune infiltration