The neuroimmunome of hepatitis patients associates with disease severity

Hepatitis is a systemic disease marked by neuroimmune dysregulation beyond hepatic inflammation. Using a systems biology approach, we conducted transcriptomic meta-analyses across in vitro models, liver tissues, and PBMCs from hepatitis virus-infected patients to identify neuroimmune signatures. We found a robust neuroimmunome signature, neuroimmune-related genes showing consistent differential expression across datasets. Functional enrichment revealed disruptions in neurotransmission (synaptic, glutamatergic, noradrenergic, neuregulin pathways) and immune signaling (cytokines, interleukin-1 response, T cell receptor, and trans-synaptic signaling). Linear discriminant analysis (LDA) showed neuroimmune genes predict disease severity. Several were also altered in hepatocellular carcinoma (HCC) samples from The Cancer Genome Atlas Program (TCGA), implicating them in oncogenic transformation. Ligand–receptor analysis revealed dysregulated neuroimmune interactions in liver tissue, notably in DBH–ADRA1A/B/D, ADRA2A/B/C, ADRB1/2/3, IL33–IL1RL1, and NRG1–ERBB4. Critically, we observed an inverse correlation between neuroimmune gene expression and inflammation markers in advanced HCC, suggesting neuroimmune suppression may support immune evasion. These findings highlight the neuroimmunome as a potential biomarker and therapeutic target in hepatitis and its complications, reinforcing the role of neuroimmune crosstalk in liver disease progression.