DHCR7 Expression Predicts Poor Outcomes and Mortality From Sepsis

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Sepsis leads to severe outcomes, including chronic critical illness (CCI) or early mortality.
• Identifying precise therapeutic targets is crucial for improving sepsis patient outcomes.

Purpose of the Study:

• Investigate lipid metabolic gene expression differences in sepsis patients based on clinical outcomes.
• Discover novel therapeutic targets for sepsis precision medicine.

Main Methods:

• Analyzed gene expression in leukocytes from sepsis patients (derivation and validation cohorts) and a zebrafish endotoxemia model.
• Utilized RNA sequencing and RT-qPCR for transcriptomic analysis.
• Tested lipid-based drugs in a zebrafish model to validate therapeutic potential.

Main Results:

• The cholesterol metabolism gene DHCR7 (7-dehydrocholesterol reductase) was significantly upregulated in sepsis patients with poor outcomes (CCI, early death) compared to rapid recovery patients.
• Upregulation of DHCR7 and other lipid genes (DHCR24, SQLEA, CYP51, MSMO1, LDLRA) was confirmed in a zebrafish sepsis model.
• The DHCR7 inhibitor AY9944 demonstrated complete rescue in a lethal zebrafish endotoxemia model.

Conclusions:

• DHCR7 upregulation in poor outcome sepsis warrants further investigation as a potential therapeutic target.
• Targeting the DHCR7 cholesterol pathway may offer a novel strategy to improve sepsis patient survival and outcomes.