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Hepatocellular carcinoma (HCC) is the main subtype of primary liver cancer with high malignancy and poor prognosis. Metabolic reprogramming is a hallmark of cancer and has great importance on the tumor microenvironment (TME). As an abundant metabolite, lactate plays a crucial role in cancer progression and the immunosuppressive TME. Nonetheless, the potential roles of lactate in HCC remain unclear. In this study, we downloaded transcriptomic data of HCC patients with corresponding clinical information from the TCGA and ICGC portals. The TCGA-HCC dataset used as the training cohort, while the ICGC-LIRI-JP dataset was served as an external validation cohort. Cox regression analysis and the LASSO regression model were combined to construct the lactate metabolism-related gene signature (LMRGS). Then, we assessed the clinical significance of LMRGS in HCC. Besides, enriched molecular functions, tumor mutation burden (TMB), infiltrating immune cells, and immune checkpoint were comprehensively analyzed in different LMRGS subgroups. In total, 66 differentially expressed lactate metabolism-related genes (LMRGs) were screened. The functions of LMRGs were mainly enriched in mitochondrial activity and metabolic processes. The LMRGS comprised of six key LMRGs (FKTN, PDSS1, PET117, PUS1, RARS1, and RNASEH1) had significant clinical value for independently predicting the prognosis of HCC patients. The overall survival and median survival of patients in the LMRGS-high group were significantly shorter than in the LMRGS-low group. In addition, there were differences in TMB between the two LMRGS subgroups. The probability of genetic mutations was higher in the LMRGS-high group. Most importantly, the LMRGS reflected the TME characteristics. In the LMRGS-high group, the immune microenvironment presented a suppressed state, accompanied by more inhibitory immune cell infiltration, including follicular helper T cells and regulatory T cells. Additionally, the expression of inhibitory checkpoint molecules was much higher in the LMRGS-high group. Our study suggested that the LMRGS was a robust biomarker to predict the clinical outcomes and evaluate the TME of patients with HCC.

A Novel Lactate Metabolism-Related Gene Signature for Predicting Clinical Outcome and Tumor Microenvironment in Hepatocellular Carcinoma