A risk model developed based on necroptosis to assess progression for ischemic cardiomyopathy and identify possible therapeutic drugs

Abstract

Object: Ischemic cardiomyopathy (ICM), with high morbidity and mortality, is the most common cause of heart failure. Cardiovascular remodeling secondary to chronic myocardial ischemia is the main cause of its progression. A recently identified type of programmed cell death called necroptosis is crucial in the development of various cardiovascular diseases. However, the function role of necroptosis in cardiac remodeling of ICM has not been elucidated. Our study aimed to screen for genes associated with necroptosis and construct a risk score to assess the progression and evaluate the prognosis of ICM patients, and further to search for potentially therapeutic drugs.Methods: The gene expression profiling was obtained from the GEO database. LASSO regression analysis was used to construct necroptosis-related gene signatures associated with ICM progression and prognosis. TF-gene and miRNA-gene networks were constructed to identify the regulatory targets of potential necroptosis-related signature genes. Pathway alterations in patients with high necroptosis-related score (NRS) were analyzed by GO, KEGG, GSEA analysis, and immune cell infiltration was estimated by ImmuCellAI analysis. CMap analysis was performed to screen potential small molecule compounds targeting patients with high NRS. Independent risk analyses were performed using nomograms.Results: Six necroptosis-related signature genes (STAT4, TNFSF10, CHMP5, CHMP18, JAK1, and CFLAR) were used to define the NRS, with areas under the ROC curves of 0.833, 0.765, and 0.75 for training test, test set, and validation set, respectively. Transcription factors FOXC1 and hsa-miR-124-3p miRNA may be regulators of signature genes. Patients with higher NRS have pathway enriched in fibrosis and metabolism and elevated nTreg cells. AZD-7762 may be an effective drug to improve the prognosis of patients with high NRS. A feature-based nomogram was constructed from which patients could derive clinical benefit.Conclusion: Our results reveal 6 necroptosis gene signatures that can evaluate the progression and prognosis of ICM with high clinical value, and identify potential targets that could help improve cardiovascular remodeling.

A novel model based on necroptosis to assess progression for polycystic ovary syndrome and identification of potential therapeutic drugs

“…TNFSF10 belongs to a family of tumor necrosis factor (TNF) ligands that induce apoptosis by binding to their receptors and triggering the activation of MAPK8/JNK, caspase 8 and caspase 3 ( 53 ). It was reported that TNFSF10 could be a marker of necroptosis in various diseases, such as ischemic cardiomyopathy and cancers ( 54 , 55 ). This study is the first to identify TNFSF10 as a diagnostic marker of necroptosis in PCOS, and its specific function in the development of PCOS needs to be further investigated.…”

Role of necroptosis and immune infiltration in preeclampsia: novel insights from bioinformatics analyses

“…Necroptosis is a novel type of programmed cell death that has been extensively investigated for its diagnostic and prognostic potential in various illnesses, such as ischemic cardiomyopathy [ 44 ], Stanford types A aortic dissection [ 45 ], and cutaneous melanoma [ 46 ]. In recent years, growing researchers have actively mined and analyzed data from GEO or other databases to find potential molecular markers for PE diagnosis and treatment.…”