Integrated Analyses of Single-Cell Transcriptome and Mendelian Randomization Reveal the Protective Role of Resistin in Sepsis Survival in Intensive Care Unit

The high morbidity and mortality rates associated with sepsis highlight the challenges of finding specific remedies for this condition in the intensive care unit (ICU). This study aimed to explore the differentially expressed genes (DEGs) specific to cell types in sepsis and investigate the role of resistin in the survival of sepsis patients through Mendelian randomization (MR) analyses. We used single-cell and bulk transcriptome data to identify cell type-specific DEGs between sepsis and healthy controls. MR analyses were then conducted to investigate the causal relationships between resistin (one of the identified DEGs) levels and the survival of sepsis patients. Additionally, we utilized meQTL (methylation quantitative trait loci) to identify cytosine-phosphate-guanine (CpG) sites that may directly affect sepsis. We identified 560 cell type-specific DEGs between sepsis and healthy controls. Notably, we observed the upregulation of resistin levels in macrophages during sepsis. In bulk transcriptome, RETN is also upregulated in sepsis samples compared with healthy controls. MR analyses revealed a negative association existed between the expression of resistin, at both gene and protein levels, and the mortality or severity of sepsis patients in ICU. Moreover, there were no associations observed between resistin levels and death or organ failure due to other causes. We also identified three methylation CpG sites, located in RETN or its promoter region—cg06633066, cg22322184, and cg02346997—that directly affected both resistin protein levels and sepsis death in the ICU. Our findings suggest that resistin may provide feasible protection for sepsis patients, particularly those with severe cases, without serious side effects. Therefore, resistin could be a potential drug candidate for sepsis treatment. Additionally, we identified two CpG sites, cg06633066 and cg22322184, that were associated with RETN protein levels and sepsis death, providing novel insights into the underlying mechanisms of sepsis.