Ketone bodies are produced by the liver from fat during fasting. We have shown that the metabolism of the ketone body acetoacetate (AcAc) restores mitochondrial function and metabolism of monocytes/macrophages exposed to acidosis. As mitochondria regulate cell sensitivity to death, we then observed that AcAc also protects cells from apoptosis and ferroptosis by increasing their reducing potential. Moreover, monocytes cultured in the presence of AcAc acquire a reparative phenotype induced by epigenetic modifications. These data suggest that AcAc behaves as a unique endogenous substrate for enhancing cell resistance to stress. The aim of this project is to characterize the metabolic, molecular and cellular mechanisms associated with this protective potential. We will decipher the metabolic and transcriptional changes that induce increased GSH and nicotinamide synthesis and the acquisition of a reparative phenotype (WP1). We will demonstrate the interest of this molecule in the context of sepsis, a pathology associated with lactic acidosis, mitochondrial dysfunction and massive cell death by (i) evaluating the potential of AcAc to resuscitate ex vivo cells from patients in septic shock (WP2) (ii) the ability of ketone bodies to reduce the severity of sepsis and protect tissues in an experimental sepsis model (WP3). This project will establish a link between metabolic reprogramming and increased tissue capacity to resist stress, and lay the foundations for evaluating its therapeutic potential in pathologies associated with massive cell death.