Hepatocyte HNF4α Deficiency Protects Against Pneumococcal Sepsis Through a Neutrophil-Dependent Mechanism

Sepsis induces profound alterations in liver function that contribute to disease progression. We previously demonstrated that peritoneal sepsis is associated with marked disruption of hepatic transcriptional programs, including loss-of-function of Hepatocyte Nuclear Factor 4 alpha (HNF4α), a master regulator of hepatic identity and metabolism. Using hepatocyte-specific HNF4α knockout mice, we further showed that loss of HNF4α is detrimental during peritoneal sepsis. Here, we investigated whether this response is conserved in pneumonia-induced sepsis and assessed its functional significance. Bulk liver RNA sequencing revealed that suppression of hepatic metabolic pathways and HNF4α target genes are conserved features of both peritoneal and Streptococcus pneumoniae-induced sepsis. Unexpectedly, hepatocyte-specific HNF4α deficiency was associated with lower bacterial burden and increased survival during pneumococcal sepsis. Mechanistically, this protective effect was dependent on neutrophils and not macrophages. These findings demonstrate that sepsis-induced hepatic HNF4α dysregulation is conserved across distinct infectious etiologies but exerts context-dependent effects on disease outcome.