Advanced tissue clearing and computational imaging has produced the first comprehensive 3D reconstructions of human liver architecture at cellular resolution, comparing healthy and cirrhotic tissue across multiple liver lobules. The technique revealed specific architectural disruptions in cirrhosis including sinusoid zonal dysregulation, reduced glutamine synthetase-expressing pericentral hepatocytes, and fragmented vascular networks—collectively indicating a shift toward "pro-portalization" where the liver's normal zonation patterns collapse. This represents a significant methodological advance beyond traditional 2D histopathology, which has been the gold standard for liver disease diagnosis but provides only cross-sectional snapshots of complex 3D structures. The findings could reshape understanding of cirrhotic progression by revealing how the liver's intricate microarchitecture—essential for proper metabolic zonation—systematically breaks down. While the study demonstrates proof-of-concept rather than therapeutic applications, the 3D approach may identify earlier biomarkers of fibrotic progression and guide more targeted treatments. The technology's main limitation is the computational complexity and specialized equipment required, which may restrict widespread clinical adoption initially. However, for liver disease research, this spatial resolution could prove transformative in understanding how architectural disruption drives functional decline.