{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T15:04:59Z","timestamp":1781708699789,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,15]]},"group-title":"Physiology","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute","award":["P30CA014051"],"award-info":[{"award-number":["P30CA014051"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  How an organism detects organ injury to initiate regeneration remains one of the central unresolved questions in regenerative biology. The liver is the only solid organ in mammals capable of complete regeneration, a process initiated by hepatocyte growth factor (\n                  <jats:italic>Hgf<\/jats:italic>\n                  ) upregulation, yet the mechanism linking liver injury to\n                  <jats:italic>Hgf<\/jats:italic>\n                  induction has been unknown. Here we identify an albumin-based sensing mechanism that continuously reports the liver\u2019s functional status to hepatic stellate cells to gate the regenerative program. Using single-molecule RNA FISH, parabiosis, and an\n                  <jats:italic>ex vivo<\/jats:italic>\n                  plasma assay, we show that stellate cells are the predominant source of\n                  <jats:italic>Hgf<\/jats:italic>\n                  and that a circulating, protein-dependent signal suppresses\n                  <jats:italic>Hgf<\/jats:italic>\n                  expression when the liver is functional. Biochemical fractionation, immunodepletion, and albumin knockout mice together demonstrate that this suppressive signal is a molecule carried by albumin rather than albumin itself. Untargeted metabolomics identified retinol as the albumin-associated suppressive molecule, which we confirm is sufficient to restore\n                  <jats:italic>Hgf<\/jats:italic>\n                  suppression in injured liver plasma. Conversely, long-chain fatty acids that rise after hepatectomy, specifically palmitate and linoleate, which compete for the same albumin binding site, are sufficient to derepress\n                  <jats:italic>Hgf<\/jats:italic>\n                  in healthy plasma. These data support a dual-input model in which albumin functions as an AND gate, integrating retinol loss and fatty acid gain as coincident indicators of liver injury before permitting\n                  <jats:italic>Hgf<\/jats:italic>\n                  derepression. Consistent with this model, acute\n                  <jats:italic>in vivo<\/jats:italic>\n                  knockdown of albumin is sufficient to derepress\n                  <jats:italic>Hgf<\/jats:italic>\n                  in stellate cells and drive liver overgrowth. These findings establish albumin as an active integrator of physiological signals that governs tissue-scale regenerative decisions and reveal that the liver is constitutively poised to regenerate, gatekept by signals that directly reflect its own functional status.\n                <\/jats:p>","DOI":"10.64898\/2026.06.10.731465","type":"posted-content","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T20:05:16Z","timestamp":1781553916000},"source":"Crossref","is-referenced-by-count":0,"title":["Albumin integrates the liver\u2019s functional status to initiate regeneration"],"prefix":"10.64898","author":[{"given":"Kristina E.","family":"Lopez","sequence":"first","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin A.","family":"Knouse","sequence":"additional","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061707450728000_2026.06.10.731465v1.1","doi-asserted-by":"crossref","unstructured":"Bangru, S. , Diegmiller, R. , Talia, S. D. & Poss, K. D . Signal control during tissue regeneration in adult animals. Nat. Rev. Mol. Cell Biol. 1\u201320 (2025).","DOI":"10.1038\/s41580-025-00917-1"},{"key":"2026061707450728000_2026.06.10.731465v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2024.07.007"},{"key":"2026061707450728000_2026.06.10.731465v1.3","first-page":"186","article-title":"Experimental pathology of the liver: Restoration of the liver of the white rat following partial surgical removal","volume":"12","year":"1931","journal-title":"Arch. Pathol"},{"key":"2026061707450728000_2026.06.10.731465v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/0270-9139(93)90510-T"},{"key":"2026061707450728000_2026.06.10.731465v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(91)92020-K"},{"key":"2026061707450728000_2026.06.10.731465v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(89)92733-2"},{"key":"2026061707450728000_2026.06.10.731465v1.7","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2004.23.592"},{"key":"2026061707450728000_2026.06.10.731465v1.8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0059836"},{"key":"2026061707450728000_2026.06.10.731465v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0403412101"},{"key":"2026061707450728000_2026.06.10.731465v1.10","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510280317"},{"key":"2026061707450728000_2026.06.10.731465v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/0270-9139(93)90237-H"},{"key":"2026061707450728000_2026.06.10.731465v1.12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116451"},{"key":"2026061707450728000_2026.06.10.731465v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(05)81018-6"},{"key":"2026061707450728000_2026.06.10.731465v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840150103"},{"key":"2026061707450728000_2026.06.10.731465v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.04.008"},{"key":"2026061707450728000_2026.06.10.731465v1.16","unstructured":"Filliol, A. et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 1\u201310 (2022)."},{"key":"2026061707450728000_2026.06.10.731465v1.17","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.14.7093"},{"key":"2026061707450728000_2026.06.10.731465v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2143(96)90064-5"},{"key":"2026061707450728000_2026.06.10.731465v1.19","doi-asserted-by":"crossref","first-page":"5494","DOI":"10.1016\/j.bbagen.2013.04.019","article-title":"Congenital analbuminaemia: Molecular defects and biochemical and clinical aspects","volume":"1830","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA) - Gen. Subj"},{"key":"2026061707450728000_2026.06.10.731465v1.20","doi-asserted-by":"publisher","DOI":"10.1021\/bi00468a012"},{"key":"2026061707450728000_2026.06.10.731465v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2015.10.014"},{"key":"2026061707450728000_2026.06.10.731465v1.22","unstructured":"Peters T . All about Albumin: Biochemistry, Genetics, and Medical Applications. (San Diego: Academic Press,1996)."},{"key":"2026061707450728000_2026.06.10.731465v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.031"},{"key":"2026061707450728000_2026.06.10.731465v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2008.04.006"},{"key":"2026061707450728000_2026.06.10.731465v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300202"},{"key":"2026061707450728000_2026.06.10.731465v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.80"},{"key":"2026061707450728000_2026.06.10.731465v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.01.038"},{"key":"2026061707450728000_2026.06.10.731465v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.017"},{"key":"2026061707450728000_2026.06.10.731465v1.29","doi-asserted-by":"crossref","unstructured":"Evans, A. et al. High Resolution Mass Spectrometry Improves Data Quantity and Quality as Compared to Unit Mass Resolution Mass Spectrometry in High-Throughput Profiling Metabolomics. Metabolomics:Open Access 04, (2014).","DOI":"10.4172\/2153-0769.1000132"},{"key":"2026061707450728000_2026.06.10.731465v1.30","doi-asserted-by":"publisher","DOI":"10.1093\/jalm\/jfz026"},{"key":"2026061707450728000_2026.06.10.731465v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0097-3"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.10.731465","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T14:45:27Z","timestamp":1781707527000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.10.731465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":31,"URL":"https:\/\/doi.org\/10.64898\/2026.06.10.731465","relation":{},"subject":[],"published":{"date-parts":[[2026,6,15]]},"subtype":"preprint"}}