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Through integrated serial transplantation, lineage tracing, single\u2010cell RNA sequencing (scRNA\u2010seq), and single\u2010cell transposase\u2010accessible chromatin sequencing (scATAC\u2010seq), we show that donor hepatocytes convert into transitional, alpha\u2010fetoprotein\u2010positive reprogrammed hepatocytes (\n                    <jats:italic>\n                      Afp\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    rHeps). These cells exhibit controlled proliferation while maintaining unipotent hepatic differentiation potential, enabling fully functional maturation after rapid expansion. Such plasticity is dynamically regulated by AFP expression level\u2010dependent metabolic remodeling through the peroxisome proliferator\u2010activated receptor \u03b3 (PPAR\u03b3) pathway, which coordinates two functionally distinct subpopulations:\n                    <jats:italic>Afp<\/jats:italic>\n                    <jats:sup>low<\/jats:sup>\n                    cells sustain proliferation by activating energy metabolism pathways, whereas\n                    <jats:italic>Afp<\/jats:italic>\n                    <jats:sup>high<\/jats:sup>\n                    cells adapt to stress by switching to \u03b2\u2010oxidation. Additionally, the proliferation of\n                    <jats:italic>\n                      Afp\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    rHeps is driven and sustained by tumor necrosis factor\u2010alpha (TNF\u2010\u03b1)\/activator protein\u20101 (AP\u20101) signaling derived from host liver neutrophils. Spatiotemporal analysis further shows that transforming growth factor\u2010beta (TGF\u2010\u03b2)\u2010mediated migration precedes PPAR\u2010driven metabolic zonation, ensuring ordered niche adaptation. Together, these findings delineate the molecular basis of liver regeneration mediated by transplanted mature hepatocytes and pinpoint the PPAR\u03b3\/AFP metabolic axis and TNF\u2010\u03b1\/AP\u20101 mitogenic signaling as actionable levers to optimize regenerative therapies based on terminally differentiated hepatocytes.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517126","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T14:42:48Z","timestamp":1769697768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Conversion of Transplanted Mature Hepatocytes into\n                    <i>Afp<\/i>\n                    <sup>+<\/sup>\n                    Reprogrammed Cells for Liver Regeneration After Injury"],"prefix":"10.1002","volume":"13","author":[{"given":"Ting","family":"Fang","sequence":"first","affiliation":[{"name":"Institute for Regenerative Medicine Medical Innovation Center and State Key Laboratory of Cardiovascular Diseases School of Life Sciences and Technology Shanghai East Hospital Tongji University  Shanghai P. 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