Nuclear receptors shape sepsis pathophysiology

Sepsis, a life-threatening syndrome caused by dysregulated host responses to infection, remains a major global health challenge with high mortality and no specific therapy. Profound disturbances in immune and metabolic homeostasis, two tightly interconnected processes regulated by nuclear receptors (NRs), are central to sepsis pathophysiology. Although NRs are well-studied in inflammatory and metabolic disorders, their roles in sepsis have been underappreciated. Emerging evidence shows that systemic inflammation suppresses multiple NRs, contributing to immune dysfunction, metabolic failure, and poor outcomes. Targeting pivotal NRs, such as hepatocyte nuclear factor 4α, retinoid X receptor, and the glucocorticoid receptor, could restore NR activity and re-establish immune-metabolic balances. This review highlights NR dysfunction in sepsis and explores biomarker and opportunities for improved patient outcomes.