Albumin integrates liver functional status to initiate regeneration
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 (Hgf) upregulation, yet the mechanism linking liver injury to Hgf induction has been unknown. Here we identify an albumin-based sensing mechanism that continuously reports the livers functional status to hepatic stellate cells to gate the regenerative program. Using single-molecule RNA FISH, parabiosis, and an ex vivo plasma assay, we show that stellate cells are the predominant source of Hgf and that a circulating, protein-dependent signal suppresses Hgf 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 Hgf 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 Hgf 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 Hgf derepression. Consistent with this model, acute in vivo knockdown of albumin is sufficient to derepress Hgf 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.