Protective Role of Cytochrome P450 Oxidoreductase in Sepsis Development: Genetic and Phenotypic Analyses

Abstract

Currently, the pathogenesis of sepsis has not been fully elucidated. This study aimed to explore the role of cytochrome P450 oxidoreductase (POR) in this disease. Specifically, two-sample Mendelian randomization, multivariate Mendelian randomization, and summary data-based Mendelian randomization methods were employed to assess the genetic impact of peripheral POR protein and POR genes from multiple tissue sources on the risk of streptococcal sepsis (ICD-10 A40) and other sepsis (ICD-10 A41). Subsequently, a mouse model of sepsis (based on lipopolysaccharide) was constructed, and the expression of POR was specifically upregulated and downregulated through AAV9-mediated overexpression and shRNA interference, respectively. Various methods were used to evaluate physiology, liver and kidney function, peripheral inflammation, and oxidative stress levels of the mice. The results of Mendelian randomization analysis showed that elevated levels of peripheral POR protein and POR genes from multiple tissues were associated with a reduced risk of other sepsis, but not with the risk of streptococcal sepsis. Animal experiments demonstrated that specific upregulation of POR expression improved the moving distance, heart rate, blood pressure, liver and kidney functions, peripheral inflammation, and oxidative stress levels in septic mice, while specific downregulation of POR expression exacerbated the above indicators. In conclusion, evidence from both genetic and animal studies indicates that POR may play an important protective role in the occurrence and development of sepsis (excluding streptococcal sepsis).