# NAC1 transcriptional activation of LDHA induces hepatitis B virus immune evasion leading to cirrhosis and hepatocellular carcinoma development

## TL;DR

This study shows how NAC1 activates LDHA to help hepatitis B virus evade the immune system, leading to liver disease and cancer.

## Contribution

The study identifies NAC1 as a novel driver of HBV immune evasion through LDHA transcriptional activation.

## Key findings

- NAC1 transcriptionally activates LDHA, promoting immune cell apoptosis and HBV immune evasion.
- NAC1 is highly expressed in HBV-infected liver cells and is linked to cirrhosis and HCC development.
- Animal studies confirm NAC1-mediated LDHA activation contributes to liver disease progression.

## Abstract

Our study aimed to elucidate the molecular mechanisms underlying NAC1 (nucleus accumbens associated 1) transcriptional regulation of LDHA and its role in HBV immune evasion, thus contributing to the development of cirrhosis and hepatocellular carcinoma (HCC). Utilizing public datasets, we performed differential gene expression and weighted gene co-expression network analysis (WGCNA) on HBV-induced cirrhosis/HCC data. We identified candidate genes by intersecting differentially expressed genes with co-expression modules. We validated these genes using the TCGA database, conducting survival analysis to pinpoint key genes affecting HBV-HCC prognosis. We also employed the TIMER database for immune cell infiltration data and analyzed correlations with identified key genes to uncover potential immune escape pathways. In vitro, we investigated the impact of NAC1 and LDHA on immune cell apoptosis and HBV immune evasion. In vivo, we confirmed these findings using an HBV-induced cirrhosis model. Bioinformatics analysis revealed 676 genes influenced by HBV infection, with 475 genes showing differential expression in HBV-HCC. NAC1 emerged as a key gene, potentially mediating HBV immune escape through LDHA transcriptional regulation. Experimental data demonstrated that NAC1 transcriptionally activates LDHA, promoting immune cell apoptosis and HBV immune evasion. Animal studies confirmed these findings, linking NAC1-mediated LDHA activation to cirrhosis and HCC development. NAC1, highly expressed in HBV-infected liver cells, likely drives HBV immune escape by activating LDHA expression, inhibiting CD8 + T cells, and promoting cirrhosis and HCC development.