Liver regeneration governed by zonated PIEZO1 mechanotransduction

Abstract Mechanical forces are recognized as regulators of organ development, homeostasis, and regeneration, yet how physical cues are sensed in a region-specific manner within the liver remains unclear. In a Science article, Zhang and colleagues identify DPP4-positive zone 2 hepatocytes as a mechanosensory population, demonstrating that mechanical stress triggers the regenerative response through PIEZO1-mediated mechanotransduction. PIEZO1 activation in these cells induces NFATC3-dependent IGFBP2 expression, establishing a molecular link between tissue mechanics and spatially coordinated proliferation. This work provides a mechanistic explanation for why regeneration originates from the mid-lobule and introduces a druggable mechanotransduction axis that might be enhanced to accelerate liver repair.