A Novel Cuproptosis-Related Signature Identified DLAT as a Prognostic Biomarker for Hepatocellular Carcinoma Patients

Background: Hepatocellular carcinoma (HCC) is the most com-mon type of liver cancers, with more than a million cases per year by 2025. Cuproptosis is a novel form of programmed cell death, and is caused by mitochondrial lipoylation and destabilization of iron-sulfur proteins triggered by copper, which was considered as a key player in various biological processes. However, the roles of cuproptosis-related genes (CRGs) in HCC remain largely unknown. Methods: In the present study, we constructed and validated a four CRGs signature for predicting the overall survival (OS) of HCC pa-tients in both The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Results: Patients with high CRGs risk score showed shorter OS than those with low CRGs risk score. Functional analysis suggested that the CRGs-based prognostic signature was associated with metabo-lism remodeling which facilitated liver cancer progression. In addi-tion, reduced infiltration of CD8+ T cells and increased macrophages were found in HCCs from patients with high CRGs risk score. As one of the four CRGs, higher expression of dihydrolipoamide S-acetyltransferase (DLAT) was accompanied by higher expression of program death ligand 1 (PD-L1) in HCC. Further, we confirmed that DLAT was up-regulated and correlated with poor prognosis in a clini-cal HCC cohort. Conclusion: In conclusion, our study constructed a four CRGs signa -ture prognostic model and identified DLAT as an independent prog-nostic factor for HCC, thus providing new clues for understanding the association between cuproptosis and HCC.