02159nas a2200373   4500000000100000000000100001008004100002260001500043653002100058653001800079653002800097653002300125100001700148700001500165700001400180700001600194700002200210700002100232700001600253700001700269700002200286700001400308700001500322700001900337700002000356700001600376700001900392700001700411245007600428856005500504300000900559520120300568022001401771       2025                            d  c2025-04-1610aAdult Stem Cells10aCell adhesion10aStem-cell biotechnology10aStem-cell research1 aRyo Igarashi1 aMayumi Oda1 aRyo Okada1 aTomoki Yano1 aSirirat Takahashi1 aStrahil Pastuhov1 aMami Matano1 aNorio Masuda1 aKazuhiro Togasaki1 aYuki Ohta1 aSaeko Sato1 aTakako Hishiki1 aMakoto Suematsu1 aManabu Itoh1 aMasayuki Fujii1 aToshiro Sato00aGeneration of human adult hepatocyte organoids with metabolic functions  uhttps://www.nature.com/articles/s41586-025-08861-y  a1-103 aProliferating hepatocytes often undergo ductal metaplasia to balance the energy trade-off between cellular functions and replication, hindering the expansion of human adult hepatocytes with functional competency1. Here we demonstrate that the combined activation of Wnt and STAT3 signalling enables long-term self-renewal of human adult hepatocyte organoids. YAP activation facilitates hepatocyte proliferation but commits it towards the biliary duct lineage. By contrast, STAT3 activation by oncostatin M induces hepatocyte proliferation while counteracting ductal metaplasia and maintaining the hepatic identity. Xenotransplanted hepatocyte organoids repopulate the recipient mouse liver and reconstitute the metabolic zonation structure. Upon niche factor removal and hormone supplementation, hepatocyte organoids form cord-like structures with bile canalicular networks and exhibit major liver metabolic functions comparable to those of in vivo hepatocytes. Hepatocyte organoids are amenable to gene editing, prompting functional modelling of inherent metabolic liver diseases. The new culture system offers a promising avenue for developing therapeutic strategies against human liver diseases.  a1476-4687