Septic cardiomyopathy (SCM) is a serious complication caused by sepsis that will further exacerbate the patient's prognosis. However, immune-related genes (IRGs) and their molecular mechanism during septic cardiomyopathy are largely unknown. Therefore, our study aims to explore the immune-related hub genes (IRHGs) and immune-related miRNA-mRNA pairs with potential biological regulation in SCM by means of bioinformatics analysis and experimental validation. MethodFirstly, screen differentially expressed mRNAs (DE-mRNAs) from the dataset GSE79962, and construct a PPI network of DE-mRNAs. Secondly, the hub genes of SCM were identified from the PPI network and the hub genes were overlapped with immune cell marker genes (ICMGs) to further obtain IRHGs in SCM. In addition, receiver operating characteristic (ROC) curve analysis was also performed in this process to determine the disease diagnostic capability of IRHGs. Finally, the crucial miRNA-IRHG regulatory network of IRHGs was predicted and constructed by bioinformatic methods. Real-time quantitative reverse transcription-PCR (qRT-PCR) and dataset GSE72380 were used to validate the expression of the key miRNA-IRHG axis. ResultThe results of immune infiltration showed that neutrophils, Th17 cells, Tfh cells, and central memory cells in SCM had more infiltration than the control group; A total of 2 IRHGs were obtained by crossing the hub gene with the ICMGs, and the IRHGs were validated by dataset and qRT-PCR. Ultimately, we obtained the IRHG in SCM: THBS1. The ROC curve results of THBS1 showed that the area under the curve (AUC) was 0.909. Finally, the miR-222-3p/THBS1 axis regulatory network was constructed. ConclusionIn summary, we propose that THBS1 may be a key IRHG, and can serve as a biomarker for the diagnosis of SCM; in addition, the immune-related regulatory network miR-222-3p/THBS1 may be involved in the regulation of the pathogenesis of SCM and may serve as a promising candidate for SCM therapy.