With a yearly burden of 11 million deaths, sepsis is a gigantic unmet medical need, caused by a host-pathogen interaction going completely wrong. Despite decades of research, the current management of sepsis remains supportive rather than curative. Clinical trials in sepsis have mainly been focused on targeting the inflammatory pathway, but without success. Our research group has found that sepsis is also accompanied with extensive hepatic metabolic perturbations. We have found that an essential transcription factor, the glucocorticoid receptor (GR), loses function in liver very early after onset. Moreover, sepsis is characterized by hyperlactatemia, which is a reliable indicator of illness severity with higher levels being predictive for a higher mortality. Interestingly, our data showed that injection of lactate is not toxic in normal, healthy mice, but when GR is compromised, this lactate induces acute lethal shock, characterized by vascular leakage, severe hypotension, organ damage, and death, all being typical features of a lethal form of sepsis. In this project, we will build further on these observations and have four aims that will be addressed. We will investigate 1) the mechanism of GR resistance, 2) how GR controls lactate levels during sepsis, 3) how GR controls lactate toxicity upon lactate injection, 4) the relevance of our observations in human sepsis patients.