Zonated mechanosensing by PIEZO1 controls liver regeneration

  • Science. 2026 Jul 2;393(6806):eaef0825. doi: 10.1126/science.aef0825.
Ying Zhang  1 ,  Yuzhuo Sun  2 ,  Guangkui Xu  3 ,  Yue Wu  1 ,  Zhijun Shi  3 ,  Zhuo Chang  3 ,  Junjun Liu  4 ,  Kaidan Pang  2 ,  Siyu Liu  2 ,  Han Wang  2 ,  Weixin Rong  1 ,  Zehua Shao  1 ,  Xingqian Liu  2 ,  Yu He  2 ,  Yang Yan  2 ,  Bin Zhou  5 ,  Zuyi Yuan  1 ,  Xu-Feng Zhang  6 ,  Stefan Offermanns  1  7  8 ,  Shengpeng Wang  1
Affiliations
  • 1. Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 2. Department of Cardiovascular Surgery, Med-X Institute, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 3. Department of Engineering Mechanics, State Key Laboratory for Strength and Vibration of Mechanical Structures, Xi'an Jiaotong University, Xi'an, China.
  • 4. Techshake Biotechnology Co., Ltd., Xi'an, Shaanxi, China.
  • 5. CAS CEMCS-CUHK Joint Laboratory, New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 6. Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 7. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 8. Center of Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany.
PMID: 42391361 DOI: 10.1126/science.aef0825
Abstract

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.

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