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Anatomists have offered many frameworks for this organization: the classical hexagonal lobule, the portal lobule, the metabolic acinus, and the modular polyhedral architecture recovered by serial reconstruction of human tissue. Position within the lobule dictates function: roughly half the hepatocyte transcriptome is zonated along the portal-to-central axis, organized by a Wnt gradient from central-vein endothelium, and the zonation is so strong that drug toxicities, steatosis, and fibrosis each strike preferentially in different zones. This review surveys the methods used to study liver architecture across scales\u2014vascular corrosion casting, serial sectioning, micro-computed tomography, tissue clearing, light-sheet microscopy, and single-cell and spatial transcriptomics\u2014and their findings, together with the computational models that attempt to integrate these scales and predict tissue-level behavior. A remarkable feature of the liver is its capacity to regenerate: lost mass and much of its architecture can be restored. Regeneration in the adult liver recapitulates much of development, raising the prospect that bioengineered and synthetic-biology approaches may eventually rescue failing human tissue. The tools to pursue this are increasingly available, though substantial gaps remain before such approaches reach the clinic.<\/jats:p>","DOI":"10.1152\/ajpgi.00133.2026","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T02:34:01Z","timestamp":1786674841000},"page":"G414-G447","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Three-dimensional architecture of the liver: structural organization, methodological advances, and functional implications"],"prefix":"10.1152","volume":"331","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4985-7710","authenticated-orcid":false,"given":"Roy","family":"Siegelmann","sequence":"first","affiliation":[{"name":"Massachusetts Institute of Technology","place":["United States"]},{"name":"Massachusetts Institute of Technology","place":["United 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