引言：需要可靠的生物标志物来预测肝细胞癌（HCC）的预后。尽管最近的证据已经确认铜平衡在肿瘤生长和进展中的关键作用，但之前没有研究过与铜相关的基因（CRG）在HCC中具有预后潜力的签名。方法：为了开发和验证HCC的CRG预后签名，我们回顾性地纳入了353名患者和142名患者作为开发和验证队列。使用具有预后价值的差异表达的CRG开发了铜相关预后签名（Copper-PSHC）。采用危险比（HR）和3年随访期内的时间相关接受者操作特征曲线下面积（AUC）评估其性能。此外，通过多变量Cox回归，将Copper-PSHC与年龄、性别和癌症分期结合构建了Copper-临床相关预后签名（Copper-CPSHC）。我们进一步通过分析体细胞突变、功能富集和肿瘤微环境来探索Copper-PSHC的潜在机制。筛选了高危组的潜在药物。结果：Copper-PSHC由9个CRG构建而成。高危组患者显示明显降低的总生存期（OS）（调整HR分别为2.65 [95% CI, 1.83-3.84]和3.30 [95% CI, 1.27-8.60] ，在开发队列和验证队列中）。Copper-PSHC在开发队列和验证队列中的OS的3年AUC分别为0.74 [95% CI, 0.67-0.82]和0.71 [95% CI, 0.56-0.86] 。Copper-CPSHC在开发队列和验证队列中的OS的3年AUC分别为0.73 [95% CI, 0.66-0.80]和0.72 [95% CI, 0.56-0.87] 。高危组显示更高的肿瘤突变负荷、调节代谢过程降低、缺氧状态和浸润的基质细胞。为高危组筛选出了六种小分子药物。结论：Copper-PSHC作为一种有前途的工具，可用于识别预后差的HCC，并通过提供潜在的临床决策支持来改善疾病预后。 版权所有 © 2023 Shi，Huang，Wang，Li，Shen，Jiang，Ran，Cai，Guo，Wang和Ren。

Introduction: Reliable biomarkers are in need to predict the prognosis of hepatocellular carcinoma (HCC). Whilst recent evidence has established the critical role of copper homeostasis in tumor growth and progression, no previous studies have dealt with the copper-related genes (CRGs) signature with prognostic potential in HCC. Methods: To develop and validate a CRGs prognostic signature for HCC, we retrospectively included 353 and 142 patients as the development and validation cohort, respectively. Copper-related Prognostic Signature (Copper-PSHC) was developed using differentially expressed CRGs with prognostic value. The hazard ratio (HR) and the area under the time-dependent receiver operating characteristic curve (AUC) during 3-year follow-up were utilized to evaluate the performance. Additionally, the Copper-PSHC was combined with age, sex, and cancer stage to construct a Copper-clinical-related Prognostic Signature (Copper-CPSHC), by multivariate Cox regression. We further explored the underlying mechanism of Copper-PSHC by analyzing the somatic mutation, functional enrichment, and tumor microenvironment. Potential drugs for the high-risk group were screened. Results: The Copper-PSHC was constructed with nine CRGs. Patients in the high-risk group demonstrated a significantly reduced overall survival (OS) (adjusted HR, 2.65 [95% CI, 1.83-3.84] and 3.30, [95% CI, 1.27-8.60] in the development and validation cohort, respectively). The Copper-PSHC achieved a 3-year AUC of 0.74 [95% CI, 0.67-0.82] and 0.71 [95% CI, 0.56-0.86] for OS in the development and validation cohort, respectively. Copper-CPSHC yield a 3-year AUC of 0.73 [95% CI, 0.66-0.80] and 0.72 [95% CI, 0.56-0.87] for OS in the development and validation cohort, respectively. Higher tumor mutation burden, downregulated metabolic processes, hypoxia status and infiltrated stroma cells were found for the high-risk group. Six small molecular drugs were screened for the treatment of the high-risk group. Conclusion: Copper-PSHC services as a promising tool to identify HCC with poor prognosis and to improve disease outcomes by providing potential clinical decision support in treatment.Copyright © 2023 Shi, Huang, Wang, Li, Shen, Jiang, Ran, Cai, Guo, Wang and Ren.