{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:55:59Z","timestamp":1777949759400,"version":"3.51.4"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Traditional hepatology conceptualizes liver cirrhosis as the linear accumulation of extracellular matrix (ECM). However, the stagnation of fibrosis reversal and the persistent risk of hepatocellular carcinoma (HCC) despite eradication of the etiology remain significant clinical challenges. We propose the \u201cChronological Decoupling\u201d hypothesis: cirrhosis arises from a specific temporal mismatch (\\Delta t &amp;gt; physiological resolution window of 7\u201314 days) between Signal A (biochemical clearance, defined as &amp;gt;50% shift of macrophages to TREM2+ restorative phenotype with MMP-9\/MMP-13 secretion) and Signal B (mechanical regeneration, defined as Piezo1-mediated YAP nuclear translocation &amp;gt;50% in hepatocytes under lateral crowding pressure). In chronic injury, Signal B is triggered prematurely before Signal A completes, producing \u201cChaotic Deconstruction\u201d quantifiable as increased ECM fragment heterogeneity, secondary inflammation markers, and covalent cross-linking via LOXL2 . This creates an immune-excluded oncogenic niche. We shift therapeutic focus from continuous anti-fibrotics to \u201cProtocol Resynchronization,\u201d a biomarker-timed sequential therapy.<\/jats:p>","DOI":"10.3389\/fonc.2026.1799039","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:25:24Z","timestamp":1777868724000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Liver cirrhosis and hepatocellular carcinoma: chronological decoupling of biochemical clearance and mechanical regeneration signals a systems biology hypothesis on programed deconstruction failure"],"prefix":"10.3389","volume":"16","author":[{"given":"Yanming","family":"Li","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University (Dezhou Hospital)","place":["Dezhou, Shandong, 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