Elevated plasma cholesterol improves sepsis outcome by promoting hepatic metabolic reprogramming

Background: Sepsis is a life-threatening condition with high mortality and limited therapeutic options. This study investigated the association between plasma cholesterol levels and sepsis survival and explored the mechanisms by which elevated cholesterol confers protection. Methods: We analyzed 2,787 sepsis patients from the MIMIC-IV database, comparing cholesterol levels between 28-day survivors and non-survivors and assessing mortality risk using multivariable Cox regression. To test causality, C57BL/6J mice were fed either a high-cholesterol diet (HCD) or a regular diet (RD) before cecal ligation and puncture (CLP). Results: Survivors had significantly higher cholesterol 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 improved survival (52.5% to 90%), through a mechanism that is not primarily explained by broad immune activation. Hepatic transcriptomics revealed metabolic reprogramming, including enhanced oxidative phosphorylation and antioxidant pathways, with suppression of endoplasmic reticulum proteostasis. Inhibition of mitochondrial respiration abolished the survival benefit. Conclusions: Elevated plasma cholesterol is associated with improved sepsis outcomes, likely through promoting hepatic metabolic reprogramming. Targeting hepatic bioenergetics is a potential therapeutic approach.