Protective impact of circulating ω-3 PUFAs on sepsis susceptibility through PCSK9 variant: evidence from Mendelian randomization and animal experiments

Background Polyunsaturated fatty acids (PUFAs), particularly ω-3 PUFAs, can improve sepsis prognosis. However, the relationship between the pre-infection levels of PUFAs and sepsis risk remains unclear. Methods We conducted a two-sample Mendelian randomization (MR) analysis using UK Biobank data to explore the causal association between circulating unsaturated fatty acids (UFAs) and sepsis susceptibility, complemented by a sepsis mouse model (cecal ligation and puncture, CLP) for validation. Results MR analysis revealed that ω-3 PUFAs (OR: 0.912, p = 0.005), ω-6 PUFAs (OR: 0.914, p = 0.036), total PUFAs (OR: 0.894, p = 0.003), and the PUFAs/MUFAs (monounsaturated fatty acids) ratio (OR: 0.927, p = 0.042) correlated with a reduced risk of sepsis, while the ω-6/ω-3 ratio increased susceptibility and mortality rates (OR: 1.084, p = 0.018). Sensitivity analyses showed no heterogeneity or horizontal pleiotropy, indicating robust findings. Ten single nucleotide polymorphisms (SNPs) were linked to both ω-3 and ω-6 PUFAs. Among which rs11591147 in the PCSK9 gene (a loss-of-function variant) may mediate the protective effect of PUFAs against sepsis. Mouse experiments showed that ω-3 PUFAs or/and the PCSK9 monoclonal antibody (evolocumab), reduced 7-day mortality (26.7, 40.0, and 53.3%, respectively) and multi-organ damage in CLP mice. Conclusion In patients with PCSK9 mutations, elevated plasma ω-3 PUFAs may reduce susceptibility to sepsis. Therefore, early detection of PUFA levels and PCSK9 genotypes, along with the targeted nutritional supplements, may help reduce sepsis risk in susceptible populations.