Mesenchymal progenitor cells (MPCs) have been hypothesized as cells of origin for sarcomas, and c-Fos transcription factor has been showed to act as an oncogene in bone tumors. In this study, we show c-Fos is present in most sarcomas with chondral phenotype, while multiple other genes are related to c-Fos expression pattern. To further define the role of c-Fos in sarcomagenesis, we expressed it in primary human MPCs (hMPCs), immortalized hMPCs and transformed murine MPCs (mMPCs). In immortalized hMPCs, c-Fos expression generated morphological changes, reduced mobility capacity and impaired adipogenic- and osteogenic-differentiation potentials. Remarkably, immortalized hMPCs or mMPCs expressing c-Fos generated tumors harboring a chondrogenic phenotype and morphology. Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation.

The gut microbiota has been implicated in glucose intolerance and its progression towards type-2 diabetes mellitus (T2DM). Relevant randomized clinical trial with prebiotic intervention was inadequate. We sought to evaluate the impact of fructooligosaccharides (FOS) and galactooligosaccharides (GOS) on glycemia during oral glucose tolerance test (OGTT) and intestinal microbiota. A randomized double-blind cross-over study was performed with 35 adults treated with FOS and GOS for 14 days (16 g/day). Faeces sampling, OGTT and anthropometric parameters were performed. Short-term intake of high-dose prebiotics had adverse effect on glucose metabolism, as in FOS intervention demonstrated by OGTT (P < 0.001), and in GOS intervention demonstrated by fasting glucose (P < 0.05). A significant increase in the relative abundance of Bifidobacterium was observed both in FOS and GOS group, while the butyrate-producing bacteria like Phascolarctobacterium in FOS group and Ruminococcus in GOS group were decreased. A random forest model using the initial microbiota was developed to predict OGTT levels after prebiotic intervention with relative success (R = 0.726). Our study alerted even though FOS and GOS increased Bifidobacterium, they might have adverse effect on glucose metabolism by reducing butyrate-producing microbes. Individualized prebiotics intervention based on gut microbiome needs to be evaluated in future.

Direct conversion technique to produce induced-neuronal (iN) cells from human fibroblasts within 2 weeks is expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression profiles in iN cells from patients with neurofibromatosis type 1 (NF1), a single-gene multifaceted disorder with comparatively high co-occurrence of autism spectrum disorder (ASD). Microarray-based transcriptomic analysis on iN cells from male healthy controls and male NF1 patients (NF1-iN cells) revealed that 149 genes expressions were significantly different (110 upregulated and 39 downregulated). We validated that mRNA of MEX3D (mex-3 RNA binding family member D) was lower in NF1-iN cells by real-time PCR with 12 sex-mixed samples. In NF1-iN cells on day 14, higher expression of FOS mRNA was observed with lower expression of MEX3D mRNA. Interestingly, BCL2 mRNA was higher in NF1-iN cells on day 5 (early-period) but not on day 14. Our data suggest that aberrant molecular signals due to NF1 mutations may disturb gene expressions, a subset of which defines continuum of the neuronal phenotypes of NF1 with ASD. Further translational studies using induced pluripotent stem (iPS) cell-derived neuronal cells are needed to validate our preliminary findings especially confirming meanings of analysis using early-period iN cells.

Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1β-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.

Using chip array assays, we identified differentially expressed genes via a comparison between luminal A breast cancer subtype and normal mammary ductal cells from healthy donors. In silico analysis confirmed by western blot and immunohistochemistry revealed that C-JUN and C-FOS transcription factors are activated in luminal A patients as potential upstream regulators of these differentially expressed genes. Using a chip-on-chip assay, we identified potential C-JUN and C-FOS targets. Among these genes, the NRIP1 gene was revealed to be targeted by C-JUN and C-FOS. This was confirmed after identification and validation with transfection assays specific binding of C-JUN and C-FOS at consensus binding sites. NRIP1 is not only upregulated in luminal A patients and cell lines but also regulates breast cancer-related genes, including PR, ESR1 and CCND1. These results were confirmed by NRIP1 siRNA knockdown and chip array assays, thus highlighting the putative role of NRIP1 in PGR, ESR1 and CCND1 transcriptional regulation and suggesting that NRIP1 could play an important role in breast cancer ductal cell initiation.

Gfi1 supports neutrophil development at the expense of monopoiesis, but the underlying molecular mechanism is incompletely understood. We recently showed that the G-CSFR Y729F mutant, in which tyrosine 729 was mutated to phenylalanine, promoted monocyte rather than neutrophil development in myeloid precursors, which was associated with prolonged activation of Erk1/2 and enhanced activation of c-Fos and Egr-1. We show here that Gfi1 inhibited the expression of c-Fos, Egr-1 and Egr-2, and rescued neutrophil development in cells expressing G-CSFR Y729F. Gfi1 directly bound to and repressed c-Fos and Egr-1, as has been shown for Egr-2, all of which are the immediate early genes (IEGs) of the Erk1/2 pathway. Interestingly, G-CSF- and M-CSF-stimulated activation of Erk1/2 was augmented in lineage-negative (Lin-) bone marrow (BM) cells from Gfi1-/- mice. Suppression of Erk1/2 signaling resulted in diminished expression of c-Fos, Egr-1 and Egr-2, and partially rescued the neutrophil development of Gfi1-/- BM cells, which are intrinsically defective for neutrophil development. Together, our data indicate that Gfi1 inhibits the expression of c-Fos, Egr-1 and Egr-2 through direct transcriptional repression and indirect inhibition of Erk1/2 signaling, and that Gfi1-mediated downregulation of c-Fos, Egr-1 and Egr-2 may contribute to the role of Gfi1 in granulopoiesis.

Synovitis in osteoarthritis (OA) is a very common condition. However, its underlying mechanism is still not well understood. This study aimed to explore the molecular mechanisms of synovitis in OA. The gene expression profile GSE82107 (downloaded from the Gene Expression Omnibus database) included 10 synovial tissues of the OA patients and 7 synovial tissues of healthy people. Subsequently, differentially expressed gene (DEG) analysis, GO (gene ontology) enrichment analysis, pathway analysis, pathway network analysis, and gene signal network analysis were performed using Gene-Cloud of Biotechnology Information (GCBI). A total of 1,941 DEGs consisting of 1,471 upregulated genes and 470 downregulated genes were determined. Genes such as PSMG3, LRP12 MIA-RAB4B, ETHE1, SFXN1, DAZAP1, RABEP2, and C9orf16 were significantly regulated in synovitis of OA. In particular, the MAPK signalling pathway, apoptosis, and pathways in cancer played the most important roles in the pathway network. The relationships between these pathways were also analysed. Genes such as NRAS, SPHK2, FOS, CXCR4, PLD1, GNAI2, and PLA2G4F were strongly implicated in synovitis of OA. In summary, this study indicated that several molecular mechanisms were implicated in the development and progression of synovitis in OA, thus improving our understanding of OA and offering molecular targets for future therapeutic advances.

Diabetic kidney disease (DKD) is a major public health issue because of its refractory nature. Ferroptosis is a newly coined programmed cell death characterized by the accumulation of lipid reactive oxygen species (ROS). However, the prognostic and diagnostic value of ferroptosis-related genes (FRGs) and their biological mechanisms in DKD remain elusive. The gene expression profiles GSE96804, GSE30566, GSE99339 and GSE30528 were obtained and analyzed. We constructed a reliable prognostic model for DKD consisting of eight FRGs (SKIL, RASA1, YTHDC2, SON, MRPL11, HSD17B14, DUSP1 and FOS). The receiver operating characteristic (ROC) curves showed that the ferroptosis-related model had predictive power with an area under the curve (AUC) of 0.818. Gene functional enrichment analysis showed significant differences between the DKD and normal groups, and ferroptosis played an important role in DKD. Consensus clustering analysis showed four different ferroptosis types, and the risk score of type four was significantly higher than that of other groups. Immune infiltration analysis indicated that the expression of macrophages M2 increased significantly, while that of neutrophils and mast cells activated decreased significantly in the high-risk group. Our study identified and validated the molecular mechanisms of ferroptosis in DKD. FRGs could serve as credible diagnostic biomarkers and therapeutic targets for DKD.

Fat deposition of beef cattle varies between breeds. However, the regulation mechanism is still not elucidated completely at molecular level. In the present study, we comparatively analyzed transcriptome of subcutaneous adipose tissue between Wagyu and Holstein cattle with a significant difference in fat deposition to identify key genes associated with fat metabolism and adipogenesis by high-throughput RNA-seq technology. A total of 59,149,852 and 69,947,982 high quality reads were generated, respectively. With further analysis, 662 differentially expressed genes were identified. Gene Ontology and KEGG pathway analysis revealed that many differentially expressed genes were enriched in several biological processes and pathways relevant to adipogenesis and lipid metabolism, in which PPAR and fatty acid metabolism signaling pathways with related genes such as PPARγ, PLIN2 and ELOVL6 et al. play a critical role. Protein-protein interaction network analysis showed EGR1, FOS, SERPINE1, AGT, MMP2 may have great impact on adipocyte differentiation and adipogenesis. Moreover, potential alternative splicing events and single nucleotide polymorphisms (SNPs) were also identified. In summary, we comprehensively analyzed and discussed the transcriptome of subcutaneous adipose tissue of Wagyu and Holstein cattle, which might provide a theoretical basis for better understanding molecular mechanism of fat metabolism and deposition in beef cattle.

Being a frequent malignant tumor of the genitourinary system, Bladder Urothelial Carcinoma (BLCA) has a poor prognosis. This study focused on identifying and validating prognostic biomarkers utilizing methylation, transcriptomics, and clinical data from The Cancer Genome Atlas Bladder Urothelial Carcinoma (TCGA BLCA) cohort. The impact of altered differentially methylated hallmark pathway genes was subjected to clustering analysis to observe changes in the transcriptional landscape on BLCA patients and identify two subtypes of patients from the TCGA BLCA population where Subtype 2 was associated with the worst prognosis with a p-value of 0.00032. Differential expression and enrichment analysis showed that subtype 2 was enriched in immune-responsive and cancer-progressive pathways, whereas subtype 1 was enriched in biosynthetic pathways. Following, regression and network analyses revealed Epidermal Growth Factor Receptor (EGFR), Fos-related antigen 1 (FOSL1), Nuclear Factor Erythroid 2 (NFE2), ADP-ribosylation factor-like protein 4D (ARL4D), SH3 domain containing ring finger 2 (SH3RF2), and Cadherin 3 (CDH3) genes to be the most significant prognostic gene markers. These genes were used to construct a risk model that separated the BLCA patients into high and low-risk groups. The risk model was also validated in an external dataset by performing survival analysis between high and low-risk groups with a p-value < 0.001 and the result showed the high group was significantly associated with poor prognosis compared to the low group. Single-cell analyses revealed the elevated level of these genes in the tumor microenvironment and associated with immune response. High-grade patients also tend to have a high expression of these genes compared to low-grade patients. In conclusion, this research developed a six-gene signature that is pertinent to the prediction of overall survival (OS) and might contribute to the advancement of precision medicine in the management of bladder cancer.

Neospora caninum is an obligate intracellular parasite that causes neurological disorders in dogs and cattle. The majority of host animals are asymptomatic at the chronic stage of infection. However, it remains unclear whether cerebral function is normal in asymptomatic animals. In this study, mice were infected with N. caninum (strain Nc-1) and their brains were examined to understand changes in cerebral function at the chronic stage of infection. Mice infected with N. caninum showed impaired locomotor activity, but no differences in clinical symptoms were observed. In the brains of infected mice, parasites were distributed throughout the brain and histological lesions were observed everywhere except for the cerebellum. Expression levels of proinflammatory cytokines, interferon-gamma and tumour necrosis factor-alpha, were highly upregulated in several brain regions of infected mice. Additionally, the level of neurotransmitters glutamate, glycine, gamma-aminobutyric acid, dopamine and 5-hydroxytryptamine, were altered in infected mice compared with those of uninfected mice. Interestingly, the expression levels of immediately early genes, c-Fos and Arc, in the brain of infected mice were lower than those of in uninfected mice. Our findings may provide insight into neurological disorders associated with N. caninum infection.

The forced swim test (FST) is widely used to screen for potential antidepressant drugs and treatments. Despite this, the nature of stillness during FST and whether it resembles "depressive-like behavior" are widely debated issues. Furthermore, despite being widely used as a behavioral assay, the effects of the FST on the brain transcriptome are rarely investigated. Therefore, in this study we have investigated changes in the transcriptome of the rat hippocampus 20 min and 24 h after FST exposure. RNA-Seq is performed on the hippocampus tissues of rats 20 min and 24 h after an FST. Differentially expressed genes (DEGs) were identified using limma and used to construct gene interaction networks. Fourteen differentially expressed genes (DEGs) were identified only in the 20-m group. No DEGs were identified 24 h after the FST. These genes were used for Gene Ontology term enrichment and gene-network construction. Based on the constructed gene-interaction networks, we identified a group of DEGs (Dusp1, Fos, Klf2, Ccn1, and Zfp36) that appeared significant based on multiple methods of downstream analysis. Dusp1 appears especially important, as its role in the pathogenesis of depression has been demonstrated both in various animal models of depression and in patients with depressive disorders.

Breast cancer (BC), as one of the leading causes of death among women, comprises several subtypes with controversial and poor prognosis. Considering the TNM (tumor, lymph node, metastasis) based classification for staging of breast cancer, it is essential to diagnose the disease at early stages. The present study aims to take advantage of the systems biology approach on genome wide gene expression profiling datasets to identify the potential biomarkers involved at stage I, stage II, stage III, and stage IV as well as in the integrated group. Three HER2-negative breast cancer microarray datasets were retrieved from the GEO database, including normal, stage I, stage II, stage III, and stage IV samples. Additionally, one dataset was also extracted to test the developed predictive models trained on the three datasets. The analysis of gene expression profiles to identify differentially expressed genes (DEGs) was performed after preprocessing and normalization of data. Then, statistically significant prioritized DEGs were used to construct protein-protein interaction networks for the stages for module analysis and biomarker identification. Furthermore, the prioritized DEGs were used to determine the involved GO enrichment and KEGG signaling pathways at various stages of the breast cancer. The recurrence survival rate analysis of the identified gene biomarkers was conducted based on Kaplan-Meier methodology. Furthermore, the identified genes were validated not only by using several classification models but also through screening the experimental literature reports on the target genes. Fourteen (21 genes), nine (17 genes), eight (10 genes), four (7 genes), and six (8 genes) gene modules (total of 53 unique genes out of 63 genes with involving those with the same connectivity degree) were identified for stage I, stage II, stage III, stage IV, and the integrated group. Moreover, SMC4, FN1, FOS, JUN, and KIF11 and RACGAP1 genes with the highest connectivity degrees were in module 1 for abovementioned stages, respectively. The biological processes, cellular components, and molecular functions were demonstrated for outcomes of GO analysis and KEGG pathway assessment. Additionally, the Kaplan-Meier analysis revealed that 33 genes were found to be significant while considering the recurrence-free survival rate as an alternative to overall survival rate. Furthermore, the machine learning calcification models show good performance on the determined biomarkers. Moreover, the literature reports have confirmed all of the identified gene biomarkers for breast cancer. According to the literature evidence, the identified hub genes are highly correlated with HER2-negative breast cancer. The 53-mRNA signature might be a potential gene set for TNM based stages as well as possible therapeutics with potentially good performance in predicting and managing recurrence-free survival rates at stages I, II, III, and IV as well as in the integrated group. Moreover, the identified genes for the TNM-based stages can also be used as mRNA profile signatures to determine the current stage of the breast cancer.

Dysregulation of the normal gene expression program is the cause of a broad range of diseases, including cancer. Detecting the specific perturbed regulators that have an effect on the generation and the development of the disease is crucial for understanding the disease mechanism and for taking decisions on efficient preventive and curative therapies. Moreover, detecting such perturbations at the patient level is even more important from the perspective of personalized medicine. We applied the Transcription Factor Target Enrichment Analysis, a method that detects the activity of transcription factors based on the quantification of the collective transcriptional activation of their targets, to a large collection of 5607 cancer samples covering eleven cancer types. We produced for the first time a comprehensive catalogue of altered transcription factor activities in cancer, a considerable number of them significantly associated to patient's survival. Moreover, we described several interesting TFs whose activity do not change substantially in the cancer with respect to the normal tissue but ultimately play an important role in patient prognostic determination, which suggest they might be promising therapeutic targets. An additional advantage of this method is that it allows obtaining personalized TF activity estimations for individual patients.

Osteoclasts can be differentiated from bone marrow-derived macrophages (BMDM). They play a key role in bone resorption. Identifying novel molecules that can regulate osteoclastogenesis has been an important issue. In this study, we found that FAM19A5, a neurokine or brain-specific chemokine, strongly stimulated mouse BMDM, resulting in chemotactic migration and inhibition of RANKL-induced osteoclastogenesis. Expression levels of osteoclast-related genes such as RANK, TRAF6, OSCAR, TRAP, Blimp1, c-fos, and NFATc1 were markedly decreased by FAM19A5. However, negative regulators of osteoclastogenesis such as MafB and IRF-8 were upregulated by FAM19A5. FAM19A5 also downregulated expression levels of RANKL-induced fusogenic genes such as OC-STAMP, DC-STAMP, and Atp6v0d2. FAM19A5-induced inhibitory effect on osteoclastogenesis was significantly reversed by a formyl peptide receptor (FPR) 2 antagonist WRW4 or by FPR2-deficiency, suggesting a crucial role of FPR2 in the regulation of osteoclastogenesis. Collectively, our results suggest that FAM19A5 and its target receptor FPR2 can act as novel endogenous ligand/receptor to negatively regulate osteoclastogenesis. They might be regarded as potential targets to control osteoclast formation and bone disorders.

A growing body of evidence implicates endoplasmic reticulum (ER) stress in the pathogenesis of chronic inflammatory and autoimmune disorders. Here, we demonstrate that the proinflammatory cytokine TNFα stimulates matrix metalloproteinase 9 (MMP9) at the ocular surface through a c-Fos-dependent mechanism of ER stress. We found positive reactivity of the molecular chaperone BiP/GRP78 in conjunctival epithelium of patients with ocular cicatricial pemphigoid and increased levels of BiP/GRP78, sXBP1 and GRP94 in human corneal epithelial cells treated with TNFα. Pharmacological blockade of ER stress in vitro using dexamethasone or the chemical chaperones TUDCA and 4PBA attenuated MMP9 expression and secretion in the presence of TNFα. Moreover, expression analysis of genes associated with inflammation and autoimmunity identified the c-Fos proto-oncogene as a mediator of ER stress responses in epithelial cells. Substantially less TNFα-induced MMP9 expression occurred when c-Fos signaling was suppressed with a function-blocking antibody. Taken together, these results indicate that activation of ER stress contributes to promote inflammation-mediated proteolytic activity and uncovers a target for restoring tissue homeostasis in ocular autoimmune disease.

Hypoxia is the most important factor in the pathogenesis of diabetic retinopathy (DR). Our previous studies demonstrated that G protein-coupled receptor 91(GPR91) participated in the regulation of vascular endothelial growth factor (VEGF) secretion in DR. The present study induced OIR model in newborn rats using exposure to alternating 24-hour episodes of 50% and 12% oxygen for 14 days. Treatment with GPR91 shRNA attenuated the retinal avascular area, abnormal neovascularization and pericyte loss. Western blot and qRT-PCR demonstrated that CoCl2 exposure promoted VEGF expression and secretion, activated the ERK1/2 signaling pathways and upregulated C/EBP and AP-1. Knockdown of GPR91 inhibited ERK1/2 activity. GPR91 siRNA transduction and the ERK1/2 inhibitor U0126 inhibited the increases in C/EBP β, C/EBP δ, c-Fos and HIF-1α. Luciferase reporter assays and a chromatin immunoprecipitation (ChIP) assay demonstrated that C/EBP β and c-Fos bound the functional transcriptional factor binding site in the region of the VEGF promoter, but not C/EBP δ. Knockdown of C/EBP β and c-Fos using RNAi reduced VEGF expression. Our data suggest that activation of the GPR91-ERK1/2-C/EBP β (c-Fos, HIF-1α) signaling pathway plays a tonic role in regulating VEGF transcription in rat retinal ganglion cells.

The aim of this work is to better understand the genetic mechanisms determining two complex traits affecting porcine meat quality: intramuscular fat (IMF) content and its fatty acid (FA) composition. With this purpose, expression Genome-Wide Association Study (eGWAS) of 45 lipid-related genes associated with meat quality traits in swine muscle (Longissimus dorsi) of 114 Iberian × Landrace backcross animals was performed. The eGWAS identified 241 SNPs associated with 11 genes: ACSM5, CROT, FABP3, FOS, HIF1AN, IGF2, MGLL, NCOA1, PIK3R1, PLA2G12A and PPARA. Three expression Quantitative Trait Loci (eQTLs) for IGF2, ACSM5 and MGLL were identified, showing cis-acting effects, whereas 16 eQTLs had trans regulatory effects. A polymorphism in the ACSM5 promoter region associated with its expression was identified. In addition, strong candidate genes regulating ACSM5, FOS, PPARA, PIK3R1, PLA2G12A and HIF1AN gene expression were also seen. Notably, the analysis highlighted the NR3C1 transcription factor as a strong candidate gene involved in the regulation of the 45 genes analysed. Finally, the IGF2, MGLL, MC2R, ARHGAP6, and NR3C1 genes were identified as potential regulators co-localizing within QTLs for fatness and growth traits in the IBMAP population. The results obtained increase our knowledge in the functional regulatory mechanisms involved in these complex traits.

Oxytocin is a neuropeptide released by the central nervous system. A number of studies have demonstrated the role of this neuropeptide in the pathogenesis of breast cancer. In the present project, we have identified mRNA coding genes and long non-coding RNAs (lncRNAs) that are associated with this pathway through an in-silico strategy, and measured their expression in a cohort of Iranian females affected with this type of malignancy. Expression levels of OXTR, FOS, ITPR1, RCAN1, CAMK2D, CACNA2D and lnc_ZFP161 were significantly down-regulated in breast cancer tissues compared with nearby non-cancerous tissues. On the other hand, expression of lnc_MTX2 was higher in breast cancer tissues compared with controls. Expression of lnc_TNS1 and lnc_FOXF1 were not different between these two kinds of samples. Expression of CACNA2D was associated with mitotic rate and PR status (P values = 3.02E-02 and 2.53E-02, respectively). Expression of other oxytocin-related genes was not associated with clinicopathological parameters. FOS and ITPR1 had the highest AUC value among the oxytocin-related genes. Combination of expression profiles of all oxytocin-related genes increased the AUC value to 0.75. However, the combinatorial sensitivity and specificity values were lower than some individual genes. In the breast cancer tissues, the most robust correlations have been detected between lnc_ZFP161/ lnc_FOXF1, CAMK2D/ lnc_ZFP161 and CAMK2D / lnc_FOXF1 (r = 0.86, 0.71 and 0.64 respectively). In the non-cancerous tissues, the strongest correlation was detected between lnc_FOXF1/lnc_MTX2 and lnc_ZFP161/CAMK2D respectively (r = 0.78 and 0.65). Taken together, oxytocin-associated genes have been dysregulated in breast cancer tissues. Moreover, the correlation ratio between these genes is connected with the existence of cancer.

Heart failure is the final destination of most cardiovascular diseases, and its complex molecular mechanisms remain largely uncertain. This study aimed to systematically investigate the underlying molecular mechanisms and diagnostic and therapeutic targets of heart failure using bioinformatics. We obtained 8 healthy samples and 8 heart failure samples from GSE8331 and GSE76701. After removing the batch effect, we performed a differential analysis on it and obtained 185 differentially expressed ID. The results of enrichment analysis showed that the molecular mechanisms of heart failure were mostly related to immune, inflammation, and metabolism-related pathways. Immune cell infiltration analysis showed that the degree of infiltration of Tgd cells and Neurons was significantly enriched in heart failure samples, whereas pDCs and NKTs were in healthy tissue samples. We obtained Hub genes including EGR1, EGR2, FOS and FOSB by PPI network analysis. We established a 4-gene diagnostic model with Hub gene, and validated it in GSE21610 and GSE57338, and evaluated the discriminative ability of Hub gene by ROC curve. The 4-gene diagnostic model has an AUC value of 0.775 in GSE21610 and 0.877 in GSE57338. In conclusion, we explored the underlying molecular mechanisms of heart failure and the immune cell infiltration environment of failing myocardium by performing bioinformatic analysis of the GEO dataset. In addition, we identified EGR1, EGR2, FOS and FOSB as potential diagnostic biomarkers and therapeutic targets for heart failure. More importantly, a diagnostic model of heart failure based on these 4 genes was developed, which leads to a new understanding of the pathogenesis of heart failure and may be an interesting target for future in-depth research.