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

Rationale: Sepsis 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. Objectives: To determine whether elevated plasma cholesterol improves sepsis survival and to elucidate the mechanistic basis of this effect. Methods: We 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 Results: Survivors had significantly higher cholesterol levels than non-survivors (median, 135 vs. 126 mg/dL, p < 0.001). High cholesterol (≥ 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. Conclusions: Elevated 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.