Together, these results characterize FoxO1 as a pivotal factor in regulating macrophage activation in response to overnutrition, suggesting that myeloid FoxO1 dysregulation is liable for linking overnutrition to abnormal macrophage activation and this effect perpetuates hepatic inflammation and catalyzes the evolution of NAFL to NASH in obesity. Here, FOXO1 is linked to metabolic dysfunction-associated steatohepatitis.