Due to progress in medical care and scientific studies, the treatment and results of sepsis have become more consistent globally. The rates of sepsis occurrence and death have shown considerable enhancement. There are no distinct indicators for diagnosis or treatment options for sepsis24.Initial research has consistently shown that elevated lactate levels indicate unfavorable results in individuals with sepsis, and it has been verified that the occurrence and fatality rates of sepsis decrease when high lactate levels are corrected during the hyperinflammatory phase25. The most recent global recommendations for treating sepsis and septic shock involve promptly monitoring and lowering serum lactate levels. It is thought that lactate contributes to immune dysfunction, especially immunoparalysis, in individuals suffering from sepsis. Certain scientists have viewed lactate as a molecule that suppresses the immune system. The discovery of lactate modification clearly explains the fundamental mechanism by which lactate regulates immune status in sepsis at the epigenetic level. The use of lactate level as an indicator of the severity or prognosis of sepsis has long been controversial. Nevertheless, lactylation is now recognized as a novel approach for determining and predicting the outcome of sepsis. Lactylation occurs in humans, animals, plants, microorganisms, and bacteria. Additionally, lactylation is controlled by lactate and works in harmony with its creation. Regulating sugar fermentation and influencing lactate production can also regulate lactylation levels. Lactylation, as a “result,” shows relative stability over time and is not affected by environmental changes, making it one of the most important clinical assessment indicators of lactylation. Most importantly, compared to lactic acid, lactylation has a dual role of “promotion” and “inhibition.” In sepsis, excessive activation of glycolysis leads to the generation and accumulation of large amounts of lactate. Metabolic enzymes in the glycolytic pathway are lactylated to suppress excessive glycolytic responses, ensuring metabolic homeostasis in the body26. Controlling lactate levels is crucial for preserving immune equilibrium within the body. Nevertheless, this feedback loop also suggests that the function of lactylation is complex. Uncovering it is just the initial phase of the investigation, with many details waiting to be explored regarding its operation. Although still in its infancy, studies on lactylation in sepsis have already demonstrated significant promise in uncovering a stronger connection between lactic acid and the immune system. Lactylation plays a significant role in oncology by affecting innate and adaptive immunity and indicating the immune status of the tumor microenvironment. This process also regulates the immune system during sepsis, and lactylation could potentially become a crucial molecule in diagnosis and treatment, replacing lactate for more effective scientific approaches.This research concentrated on examining the activity of lactylation genes in individuals with sepsis, investigating the potential prognostic and diagnostic significance of these genes in sepsis. RNA sequencing of peripheral blood from septic patients and normal individuals was conducted in a preliminary study. Differentially expressed genes were identified from the sequencing results, and the intersection between the differentially expressed genes and lactylation genes was determined to identify lactylation genes associated with sepsis. Through gene ontology analysis, it can be inferred that these cross-genes are mainly associated with cellular components, such as cells and cell junctions, and the molecular functions enriched in cross-genes are predominantly related to binding and catalytic activity. Biological adhesion and regulation are the primary biological processes linked to cross-genes. According to the KEGG analysis, amino acid metabolism and immune diseases were the most significant pathways involving multiple genes. Subsequently, PPI was used to screen for core genes. We verified the gene expression levels by downloading sepsis-related datasets from GEO. It was found that lactylation genes (S100A11, CCNA2) have significant potential for the diagnosis, prognosis assessment, and guidance of sepsis.S100A11, also known as S100 calcium-binding protein A11, is a gene that encodes a protein. The gene contains a protein from the S100 group with two EF-hand calcium-binding motifs27. The S100 gene encodes proteins in the cytoplasm and nucleus of different types of cells. They are essential for controlling various cellular functions, such as advancing through the cell cycle and specializing. There are at least 13 members in the S100 gene family, all clustered-on chromosome 1q21. This gene’s protein product could play a role in movement, penetration, and the formation of tubulin polymers. Changes in the expression of this gene and chromosomal rearrangements have been linked to the spread of tumors to other parts of the body. Although S100A11 has been implicated in tumor development in previous studies28, recent research has found that S100A11 is upregulated in patients with sepsis29. Upon analysis of the relationship with immune infiltrating cells, it was noted that variations in expression were primarily linked to elevated levels of macrophage and neutrophil infiltration and reduced levels of T cell (CD4, CD8) infiltration. Ultimately, it was discovered that S100A11 can independently affect the prognosis of patients29. Our findings align with this outcome. In this study, we identified the core gene S100A11 by intersecting the differential genes of sepsis with the lactylation genes. The expression of the lactylation gene S100A11 was verified at the gene expression level by downloading datasets related to sepsis from the GEO database. The analysis of our survival data revealed that patients with low levels of S100A11 had a lower 28-day survival rate compared to those with high levels, indicating a negative association with sepsis patient survival rates. This information was obtained from GSE65682. Analysis of the ROC curve using the GSE69528 dataset from the GEO database indicated that S100A11 exhibits elevated levels of sensitivity and specificity, achieving an AUC of 0.961. An analysis combining various datasets found that S100A11 expression was significantly higher in sepsis survivors than non-survivors, with a P-value below 0.05. Finally, single-cell sequencing analysis revealed that S100A11 was highly expressed in monocyte macrophages. Our research began with lactylation as the starting point and ultimately identified the lactylation gene (S100A11) as having significant potential in the diagnosis, prognosis, and guidance for sepsis.CCNA2 (Cyclin A2) is a protein-coding gene. The cyclin family, which regulates the cell cycle, is activated by this gene protein to promote the G1/S and G2/M transition via cyclin-dependent kinase 230. Diseases associated with CCNA2 include Retinoblastoma31and Adenocarcinoma32. Researchers discovered that the level of CCNA2 expression in sepsis is closely linked to the SOFA score and mortality rate, as revealed by Gene expression profiling. Our research identified the core gene CCNA2 by sorting the lactylation genes and differential genes associated with sepsis using bioinformatics methods. The analysis of our survival data showed that patients with low levels of CCNA2 had a higher 28-day survival rate compared to those with high levels, which was associated with better survival outcomes in sepsis patients, and this difference was statistically significant (P < 0.05). Based on the ROC curve results of the GSE69528 dataset in the GEO database, CCNA2 exhibited high sensitivity and specificity. Additionally, a meta-analysis confirmed that CCNA2 is decreased in the sepsis survival group but increased in the non-survival group. Single-cell sequencing ultimately showed that CCNA2 is mainly found in immune cells, specifically NK cells, T cells, and B cells. Our study found that it can provide a deeper connection between lactylation and sepsis immunology.Conclusion and limitationsThis study investigated sepsis differential genes with lactylation genes to identify lactylation genes related to sepsis. Several datasets were obtained from the GEO repository to validate the core genes. Our study identified lactylation genes closely associated with sepsis, which may serve as reference indicators for sepsis diagnosis, prognosis assessment, and guidance. Nevertheless, our research is constrained by a limited sample size, restricted to gene-level speculation, and lacks further investigation into underlying mechanisms.
