Elevated plasma cholesterol causally improves sepsis outcome by promoting hepatic metabolic reprogramming

RationaleSepsis is a life-threatening condition with high mortality and limited therapeutic options. While hypocholesterolemia is associated with poor outcomes, the causal role of cholesterol and its underlying mechanisms remain unclear. ObjectivesTo determine whether elevated plasma cholesterol improves sepsis survival and to elucidate the mechanistic basis of this effect. MethodsWe analyzed septic patients from the MIMIC-IV database. Total cholesterol levels were compared between 28-day survivors and non-survivors using Wilcoxon rank-sum tests. Cox proportional hazards regression assessed the association between cholesterol levels and mortality, adjusting for age, sex, race, SOFA score, and Charlson comorbidity index. To establish causality, C57BL/6J mice were randomized to receive either a high-cholesterol diet (HCD) or regular diet (RD) for three days prior to cecal ligation and puncture (CLP) to induce sepsis. Measurements and Main ResultsSurvivors had significantly higher cholesterol levels than non-survivors (median, 135 vs. 126 mg/dL, p < 0.001). High cholesterol ([&ge;] 133 mg/dL) was independently associated with reduced 28-day mortality (adjusted HR = 0.80, 95% CI: 0.67-0.95, p = 0.012). In mice, HCD elevated plasma cholesterol and significantly improved survival (52.5% to 90%), independent of immune modulation.Hepatic transcriptomics revealed metabolic reprogramming, including upregulation of oxidative phosphorylation and glutathione-mediated antioxidant pathways, and suppression of endoplasmic reticulum proteostasis. Notably, inhibition of mitochondrial respiration abolished the survival benefit. ConclusionsElevated plasma cholesterol causally improves sepsis outcomes by promoting hepatic metabolic reprogramming. These findings offer mechanistic insight into clinical observations and suggest hepatic bioenergetics as a novel therapeutic target in sepsis.