Targeting the ELF1-HGFAC axis via Normothermic Machine Perfusion (NMP) rescues regenerative capacity in human Acute-on-Chronic Liver Failure

Background: Acute-on-chronic liver failure (ACLF) is associated with overwhelming systemic inflammation and high waitlist mortality. While liver transplantation (LT) remains the only definitive treatment, it is severely limited by organ shortage. Understanding the molecular mechanisms that brake native liver regeneration could identify novel therapeutic strategies to bridge patients to transplantation or recondition marginal liver grafts.
Methods: We performed comparative transcriptomics on distinct clinical ACLF cohorts to identify core drivers of regenerative failure, validating findings in murine models. Crucially, to evaluate translational potential for the transplant setting, we utilized a diseased human split-liver normothermic machine perfusion (NMP) platform. This ex vivo system modeled two clinical scenarios: simulating inflammatory storms (LPS/D-Gal) in decompensated cirrhotic livers, and testing the therapeutic efficacy of recombinant HGFAC (rh-HGFAC) on explanted human ACLF livers.
Results: Transcriptomic analysis identified Hepatocyte growth factor activator (HGFAC) deficiency as a core feature of ACLF, inversely correlating with clinical severity and waitlist mortality. Mechanistically, inflammation-induced ELF1 repressed HGFAC transcription, driving pro-inflammatory macrophage polarization and arresting regenerative signaling (Notch, WNT, mTORC1). In our human split-liver NMP model, perfusion of explanted ACLF livers with rh-HGFAC successfully dampened inflammation and mitigated hepatocellular injury. Importantly, rh-HGFAC treatment during NMP restored graft metabolic viability (enhanced lactate clearance) and reactivated parenchymal proliferation (Ki67⁺).
Conclusion: The ELF1-HGFAC axis acts as a critical checkpoint linking immune activation to regenerative failure. For the transplant community, reconstituting HGFAC activity represents a potent pharmacological strategy. Administered systemically or delivered ex vivo via NMP, it holds significant promise for rehabilitating expanded-criteria or diseased donor livers, and rescuing native liver function to defer the need for urgent transplantation.