<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.本研究旨在探究肠道菌群通过过氧化物酶1（PRDX1）介导的代谢重编程在肝细胞癌（HCC）免疫逃逸中的驱动作用。通过对临床样本的多组学分析及细胞与动物模型的实验验证，我们发现HCC患者体内杆菌纲（Bacilli）和乳杆菌目（Lactobacillales）显著富集，这与PRDX1上调（log2FC=2.1，p<0.001）及糖酵解通路激活密切相关。机制上，杆菌纲感染可诱导PRDX1过表达（4.6倍，p<0.001），进而导致乳酸分泌增加（2.3倍，p<0.01），并通过下调NKG2D配体及细胞毒性标志物（CD107a和IFN-γ降低45%-52%）抑制自然杀伤（NK）细胞功能。重要的是，通过PRDX1敲低或糖酵解抑制（2-DG）靶向该通路可逆转上述效应，并在体内恢复PD-1抗体的疗效（改善40%，p<0.01）。这些发现首次建立了特定肠道菌群、PRDX1驱动的代谢改变与HCC中NK细胞功能障碍之间的直接关联，为通过调控肿瘤微环境中的菌群-代谢-免疫轴以克服免疫治疗耐药性提供了机制基础。