As sepsis hits 49 million people per year, killing 11 million of them, it is the most urgent unmet medical condition of today. In the best mouse model of sepsis, the CLP model, we have found that lethality is linked to loss of function of the transcription factor PPARa in hepatocytes. PPARa is the coordinator of fatty acid beta oxidation and ketogenesis, i.e. the transformation of free fatty acids (FFAs) into acetyl-coA and ketone bodies (KBs). In sepsis, FFAs are massively released from fat and so they accumulate in tissues because they are not transformed to KBs. These latter are essential to prevent coma and heart failure. RNA sequencing (RNASEQ) of livers from septic mice, revealed that the decline in PPARa mRNA is strongly predicted to depend on a progressive failure of HNF4a, a key transcriptional regulator of hepatocyte differentiation. So, in sepsis, the loss of HNF4a function leads to de-differentiation of hepatocytes, which is reflected in decreased expression of many other genes, i.e. cytochrome p450 (Cp450) coding genes. The cause of the HNF4a failure and de-differentiation of the liver and the role it plays in the progression of sepsis form the basis of this project.Using mice, we will investigate the role that HNF4a plays in sepsis and on the mechanism of the loss of function of HNF4a: we will study basic aspects of the transcription factor biology of HNF4a during sepsis, and the role of FFAs in the inhibition of HNF4a by spatial RNASEQ transcriptomics using normal, mutant and humanized mice. The impact of HNF4a problems on Cp450 function will be studied as a cause of rise of endogenous metabolites and their role in sepsis. New HNF4a ligands will be identified by screening and a new sepsis biomarker defined. Therapeutic interventions will be explored using PPARa stimuli and KBs, and validation of our data towards human sepsis will happen via a twostep strategy involving a pig sepsis model and the collection and study of human sepsis liver biopsies.