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 the fibrotic liver triggeres antigen-independent abnormal DC maturation, characterized by elevated co-stimulatory molecules, impaired phagocytic capacity, reduced IL-10 secretion, and suppressed regulatory T cell (Treg) differentiation. Mechanistically, the stiff ECM inhibites the AMPK-LXRα-ABCG1 signaling axis in DCs, reducing cholesterol efflux and promoting intracellular cholesterol accumulation. Cholesterol depletion or AMPK activation reverses stiffness-induced abnormal DC maturation. In mouse models, combined treatment with pirfenidone and simvastatin reduced liver stiffness and collagen deposition, and restored immune tolerance by correcting DC cholesterol metabolism. Our study identifies a mechanometabolic pathway linking matrix stiffness to DC dysfunction, providing a promising immunometabolic strategy for antifibrotic therapy.