RXRα suppression drives hepatic metabolic and immune dysfunction in sepsis

Sepsis is a life-threatening condition in which a dysregulated host response to infection leads to organ dysfunction and metabolic and immune failure. We identify hepatocyte retinoid X receptor α (RXRα) as a key integrator of host resilience during polymicrobial sepsis. RXRα is transcriptionally regulated by hepatocyte nuclear factor 4α (HNF4α), and sepsis rapidly decreases RXRα mRNA and protein levels. Transcriptomic analyses show that the septic liver becomes partially resistant to pharmacological activation of RXRα with bexarotene. Prophylactic- but not therapeutic- bexarotene improves survival by preserving metabolic stability and enhancing bacterial clearance. In hepatocyte-specific inducible RXRα-deficient mice, this protection is lost, confirming dependence on hepatocyte RXRα. Loss of RXRα in hepatocytes reduces Kupffer cell numbers, resulting in bacterial dissemination and mortality, a phenotype reproduced in a genetic model of selective Kupffer cell ablation. Overall, RXRα maintains the hepatic macrophage niche, linking hepatocellular transcriptional competence to systemic antibacterial defense.