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However, their fibrosis-independent and homeostatic functions remain poorly understood\n                    <jats:sup>1\u20135<\/jats:sup>\n                    . Here we demonstrate that genetic depletion of HSCs changes WNT activity and zonation of hepatocytes, leading to marked alterations in liver regeneration, cytochrome P450 metabolism and injury. We identify R-spondin 3 (RSPO3), an HSC-enriched modulator of WNT signalling, as responsible for these hepatocyte-regulatory effects of HSCs. HSC-selective deletion of\n                    <jats:italic>Rspo3<\/jats:italic>\n                    phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, liver size, regeneration and cytochrome P450-mediated detoxification, and exacerbates alcohol-associated and metabolic dysfunction-associated steatotic liver disease.\n                    <jats:italic>RSPO3<\/jats:italic>\n                    expression decreases with HSC activation and is inversely associated with outcomes in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These protective and hepatocyte-regulating functions of HSCs via RSPO3 resemble the R-spondin-expressing stromal niche in other organs and should be integrated into current therapeutic concepts.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-08677-w","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T12:03:05Z","timestamp":1741780985000},"page":"752-761","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":140,"title":["Hepatic stellate cells control liver zonation, size and functions via 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