Zonated mechanosensing by PIEZO1 controls liver regeneration

The liver exhibits a marked regenerative capacity organized through distinct zones, yet how tissue mechanics coordinate zonated proliferation remains elusive. We reveal that mechanical cues critically contribute to mouse liver regeneration in a highly region-specific manner through sensing by a subpopulation of mid-lobular hepatocytes, which are characterized by dipeptidyl peptidase-4 (DPP4) expression and represent the key proliferative pool of hepatocytes. PIEZO1 is a primary mechanosensor enriched in zone 2 DPP4 + hepatocytes that integrates biomechanical cues to drive liver regrowth by insulin-like growth factor binding protein 2 (IGFBP2). Genetic disruption of PIEZO1 restrains hepatocyte proliferation and compromises liver regeneration, whereas zonated PIEZO1 gain of function enhances proliferation and accelerates recovery. These findings reveal that DPP4 + mechanosensitive hepatocytes orchestrate liver regrowth through PIEZO1-mediated mechanosensing, establishing a link between tissue mechanics and liver regeneration.