Hepatic hypertension on-a-chip identifies GPR116 as a hydrostatic pressure mechanosensor to regulate vascular injury in cirrhosis.

Cirrhosis-associated portal hypertension drives vascular injury, yet the pathogenesis mediated by abnormal hydrostatic pressure (HP) remains unclear due to the absence of in vitro models replicating the cirrhotic perivascular mechanical microenvironment. Here, we developed 2D static and 3D dynamic "hepatic hypertension on-a-chip" (HH chip) systems replicating cirrhotic hemodynamics and matrix properties. The HH chip realized integration and decoupled regulation of HP, shear stress, and matrix stiffness. Liver sinusoidal endothelial cells (LSECs) exhibited HP-induced damage exclusively on stiff matrices, recapitulating cirrhotic degeneration phenotypes and genotypes. Using the HH chip, we identified GPR116 as the key HP mechanosensor in LSECs and delineated its downstream mechanotransduction pathway driving cellular injury. Genetic silencing of GPR116 protected endothelial cells from HP-induced damage both in vitro and in cirrhotic murine models. Cell- and gene-based therapies targeting GPR116 significantly attenuated cirrhosis progression. The HH chip can accelerate pathological investigation, target identification, and therapeutic development for hypertension-associated diseases.