<b>Single-Cell Multiomics Reveals How Gut Microbiota Reprogram Hepatocellular Carcinoma Metabolism to Suppress NK Cell Surveillance Through PRDX1</b>

This study investigates the role of gut microbiota in driving immune evasion in hepatocellular carcinoma (HCC) through peroxiredoxin 1 (PRDX1)-mediated metabolic reprogramming. Using multi-omics analysis of clinical samples and experimental validation in cell and animal models, we demonstrate that HCC patients exhibit significant enrichment of Bacilli and Lactobacillales, which correlates with PRDX1 upregulation (log2FC=2.1, p&lt;0.001) and glycolytic pathway activation. Mechanistically, Bacilli infection induces PRDX1 overexpression (4.6-fold, p&lt;0.001), leading to increased lactate secretion (2.3-fold, p&lt;0.01) and suppression of NK cell function through downregulation of NKG2D ligands and cytotoxicity markers (CD107a and IFN-γ reduced by 45-52%). Importantly, targeting this pathway through PRDX1 knockdown or glycolysis inhibition (2-DG) reverses these effects and restores PD-1 antibody efficacy in vivo (40% improvement, p&lt;0.01). These findings establish for the first time a direct link between specific gut microbiota, PRDX1-driven metabolic alterations, and NK cell dysfunction in HCC, providing a mechanistic basis for novel therapeutic strategies to overcome immunotherapy resistance by modulating the microbiota-metabolism-immune axis in the tumor microenvironment.