Glucocorticoids trigger muscle-liver crosstalk to attenuate acute liver injury and promote liver regeneration via the FGF6-FGFBP1 axis

Background: Acute liver injury (ALI) requires rapid hepatic regeneration to avert fatal liver failure. As key mechanisms, systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process. Skeletal muscle, as a major metabolic organ system, undergoes significant remodeling during ALI. However, its specific regulatory contributions remain largely uncharacterized. Methods: Partial (2/3) hepatectomy and acetaminophen were used to induce ALI in male mice. RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin by sequencing (ATAC-seq), chromatin immunoprecipitation, luciferase assay, Western blotting, TUNEL assay, immunohistochemistry, and phase separation assays were performed to reveal the transcriptional axis involved. Serum fibroblast growth factor binding protein 1 (FGFBP1) protein levels in ALI patients were assessed via enzyme-linked immunosorbent assay. Results: Integrated analysis of RNA-seq and ATAC-seq following ALI identifies glucocorticoid (GC) signaling-mediated regulation of fibroblast growth factor 6 (FGF6) in skeletal muscle metabolism. Muscle-specific knockdown of GC receptor (GR) exacerbates ALI and suppresses liver regeneration. Fgf6-knockout mice exhibited improved ALI and enhanced liver regeneration, with intramuscular injection of FGF6-neutralizing antibody rescuing the detrimental effects induced by GR knockdown. Further analysis of the FGF6 downstream target revealed that FGF6 regulates FGFBP1 expression through extracellular signal regulated kinase-activating transcription factor 3 signaling. Moreover, FGF6 regulates the heparin-dependent release kinetics of FGFBP1 by perturbing its liquid–liquid phase separation (LLPS)-driven condensate dynamics at the plasma membrane. Circulating FGFBP1 subsequently interacts with hepatic fibroblast growth factor 5 (FGF5) through LLPS mechanisms to regulate liver regeneration. Conclusion: Our results demonstrate a molecular mechanism by which muscle-liver crosstalk can initiate and sustain liver regeneration via the FGF6-FGFBP1/FGF5 axis, providing a potential therapeutic target and treatment strategy for ALI.