With the obesity epidemic, global prevalence of non-alcoholic fatty liver disease (NAFLD) is currently at 25% and rising. NAFLD patients are also at increased risk of developing secondary pathologies, including infections and paracetamol-induced liver damage, although the mechanisms behind this remain unclear. As no pharmacological treatment of NAFLD exists, patients are typically instructed to lose weight to alleviate symptoms. However, it is unclear if weight loss alone is sufficient to restore liver homeostasis or if recovered NAFLD patients remain more susceptible to secondary pathologies. The host labs have identified cell-cell circuits that control the functional specialization of liver macrophages in the steady-state and fatty liver. NAFLD could lead to tissue memory by disrupting these interactions and establishing aberrant cell-cell circuits that maintain a pathological state even after weight loss. Such NAFLD memory could facilitate the relapse into NAFLD but also modulate susceptibility to secondary insults. Indeed, my preliminary data indicates altered susceptibility to paracetamol overdose. Here, I propose to use single-cell RNA sequencing and epigenetics to investigate how cell circuits in the liver are perturbed after NAFLD regression and identify the signals underlying these alterations. Ultimately this project could provide therapeutic avenues to ‘reset’ pathogenic liver circuits in patients currently suffering from NAFLD or those in the process of recovery.