Cross-Species Hepatic Transcriptomics Identify Conserved Immune-Metabolic Reprogramming in Acute-on-Chronic Liver Failure Progression

Panyu Chen¹Yun Song¹Xiao Lin²Zhaokai Zeng²Wenxi Su³Yunyun Ren³Chen Wang^1*Kang He^2*Min Shi^1*Yugang Wang^1*

• ¹Tongren Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
• ²Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
• ³Shanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, China

Background: Acute-on-chronic liver failure is a fatal syndrome involving sudden hepatic deterioration in patients with chronic liver disease, resulting in high short-term mortality. The intrahepatic molecular mechanisms that drive disease progression are poorly understood, partly due to limited access to human liver tissues. Method: Transcriptomic profiling of liver tissues from patients with hepatitis B virus-related acute-on-chronic liver failure and a corresponding murine model was performed. Comparative analyses were conducted across disease stages to delineate the dynamic immune and metabolic trajectories. Result: The analysis uncovered a conserved immune-metabolic dysregulation during disease progression. In both patients and mice, immune activation-characterized by monocyte and macrophage infiltration and altered cytokine signaling-coincided with progressive metabolic failure, including the suppression of mitochondrial functions. The murine model further demonstrated a transition from an early stage of hyperinflammation to a later stage of immune exhaustion. Moreover, several monocyte and macrophage-associated genes were identified as conserved markers that correlate with disease severity, highlighting their potential as biomarkers or therapeutic targets. Conclusion: This study defines a conserved immune-metabolic interplay during the progression of hepatitis B virus-related acute-on-chronic liver failure and validates the murine model's accuracy for studying the disease's terminal stage. The identified dysregulation of immune cells and metabolic pathways presents actionable targets for developing stage-specific therapies intended to disrupt the disease's vicious immune-metabolic cycle.