{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:26:13Z","timestamp":1785432373173,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372603"],"award-info":[{"award-number":["82372603"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172900"],"award-info":[{"award-number":["82172900"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82372603"],"award-info":[{"award-number":["82372603"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82172900"],"award-info":[{"award-number":["82172900"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Shanghai Leading Talent Program of Eastern Talent Plan","award":["BJJY2024068"],"award-info":[{"award-number":["BJJY2024068"]}]},{"name":"Chinese Society of Clinical Oncology (CSCO)-Chaoyang Oncology Research Foundation","award":["Y-Young2021-0015"],"award-info":[{"award-number":["Y-Young2021-0015"]}]},{"name":"Research physician project from Shanghai Jiao Tong University School of Medicine","award":["20191901"],"award-info":[{"award-number":["20191901"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The human liver is a polyploid organ, dominantly featured by a high proportion of binuclear polyploid hepatocytes. Our recent study demonstrates that decline of the abundance of binuclear hepatocytes (ABH) plays a critical role in contributing to Hepatocellular carcinoma (HCC) formation, involving the cytokinesis regulator Anillin. However, the relevance between liver stiffness and the acquired ABH attenuation remains unclear. In this study, we set a mechanical environment gel with different gradients to simulate different liver stiffness environments, combined with the paired paracancerous liver tissues from real-world patients with HCC who underwent radical surgery. A mechanosensitive Piezo1\/RUNX2\/Anillin axis was discovered. As observed, the decline of ABH in paracancerous liver tissues is a noteworthy measurable value for tumor formation, correlated with the extent of liver matrix stiffness and dismal phenotypes. A stiffened culture environment may promote quick polyploid attenuation of hepatocytes, accompanied by high expression of Piezo1, a critical mechanosensitive ion channel, and a consequential nuclear translocation of RUNX2. Importantly, RUNX2 functions as an upstream transcription factor of Anillin. Regulating Piezo1\/RUNX2 or using Piezo1 agonist remarkably affected Anillin expression and hepatocyte polyploidy homeostasis. Thus, we propose that the Piezo1\/RUNX2\/Anillin axis transduces the microenvironment mechanical signal from liver stiffening and impairs hepatocyte polyploidy homeostasis in HCC formation.<\/jats:p>","DOI":"10.3390\/ijms27114685","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T16:06:08Z","timestamp":1779465968000},"page":"4685","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Liver Matrix Stiffening Modulates Tumor-Associated Hepatocyte Polyploid Homeostasis via Piezo1\/RUNX2\/Anillin Mechanosensitive Axis"],"prefix":"10.3390","volume":"27","author":[{"given":"Xinyi","family":"Luo","sequence":"first","affiliation":[{"name":"Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui Jin Er Road, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui Jin Er Road, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiquan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui Jin Er Road, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0685-4384","authenticated-orcid":false,"given":"Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6734-265X","authenticated-orcid":false,"given":"Fengjie","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui Jin Er Road, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui Jin Er Road, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Fei","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui Jin Er Road, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1068-9499","authenticated-orcid":false,"given":"Junqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui Jin Er Road, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/s41586-025-08861-y","article-title":"Generation of human adult hepatocyte organoids with metabolic functions","volume":"641","author":"Igarashi","year":"2025","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.celrep.2014.08.046","article-title":"Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation","volume":"9","author":"Alder","year":"2014","journal-title":"Cell Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s12935-023-02992-w","article-title":"Tumor matrix stiffness provides fertile soil for cancer stem cells","volume":"23","author":"Safaei","year":"2023","journal-title":"Cancer Cell Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114448","DOI":"10.1016\/j.addr.2022.114448","article-title":"Multiscale biomechanics and mechanotransduction from liver fibrosis to cancer","volume":"188","author":"Li","year":"2022","journal-title":"Adv. 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