Hepatic Fibrosis Extracellular Matrix Stiffness Induces Abnormal Maturation of Dendritic Cell via AMPK Inhibition-Mediated Cholesterol Accumulation

Dendritic cell (DC)-based immunotherapy shows limited efficacy against hepatic fibrosis, and the underlying mechanometabolic crosstalk remains unclear. Here, from a mechanobiological perspective, we demonstrate that increased extracellular matrix (ECM) stiffness in fibrotic liver triggered antigen-independent abnormal DC maturation, characterized by elevated co-stimulatory molecules, impaired phagocytic capacity, reduced IL-10 secretion, and suppressed regulatory T cell (T reg ) differentiation. Mechanistically, stiff ECM inhibited the AMPK-LXRα-ABCG1 signaling axis in DCs, reducing cholesterol efflux and promoting intracellular cholesterol accumulation. Cholesterol depletion or AMPK activation reversed stiffness-induced abnormal DC maturation. In mouse models, combined treatment with pirfenidone and simvastatin reduced liver stiffness, collagen deposition, and restored immune tolerance by correcting DC cholesterol metabolism. Our study identified a mechanometabolic pathway linking matrix stiffness to DC dysfunction, providing a promising immunometabolic strategy for antifibrotic therapy.