Macrophage MERTK restrains GRAMD1A-driven mitochondrial oxysterol trafficking to limit colitis.

Impaired macrophage efferocytosis drives chronic inflammation, yet the underlying immunometabolic mechanisms remain poorly defined. In this study, we identify that impaired macrophage efferocytosis triggers excessive mitochondrial oxysterol accumulation, which drives mitochondrial ROS-associated inflammation in Crohn's disease (CD). We report an inverse correlation between CD activity and the abundance of MERTK+ macrophages. Mechanistically, MERTK loss enhances cholesterol biosynthesis in the endoplasmic reticulum (ER) and stabilizes the cholesterol transporter GRAMD1A. This promotes excessive cholesterol trafficking from the ER to mitochondria. Within mitochondria, this cholesterol is metabolized into specific oxysterols that, unlike other mevalonate pathway metabolites, directly impair the electron transport chain. This impairment triggers a burst of mitochondrial reactive oxygen species (ROS). Collectively, our findings define a pathogenic axis linking defective efferocytosis, dysregulated cholesterol metabolism, and oxysterol-induced mitochondrial damage.