Liver cirrhosis and hepatocellular carcinoma: chronological decoupling of biochemical clearance and mechanical regeneration signals a systems biology hypothesis on programed deconstruction failure

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 “Chronological Decoupling” hypothesis: cirrhosis arises from a specific temporal mismatch (Δ t > physiological resolution window of 7–14 days) between Signal A (biochemical clearance, defined as >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 >50% in hepatocytes under lateral crowding pressure). In chronic injury, Signal B is triggered prematurely before Signal A completes, producing “Chaotic Deconstruction” 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 “Protocol Resynchronization,” a biomarker-timed sequential therapy.