He Miaolong, Wang Xiaole, Xu Xiaolei, Wang Xiaojuan, Wang Xixin, Feng Xiaobin
Department of Hepatopancreatobiliary, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China.
Department of Oncology, Binzhou Medical University Hospital, Binzhou, China.
Dig Dis Sci. 2025 Jul 1. doi: 10.1007/s10620-025-09185-7.
Hypoxia and mitochondrial dysfunctions are key contributors to the progression of liver hepatocellular carcinoma (LIHC). This study aimed to investigate the roles of hypoxia and mitochondrial energy metabolism-related differentially expressed genes (HMEMRDEGs) in the prognosis of LIHC.
HMEMRDEGs were identified from the LIHC cohort from the Cancer Genome Atlas (TCGA) dataset by intersecting DEGs from TCGA-LIHC with hypoxia-related genes (HRGs) and mitochondrial energy metabolism-related genes (MEMRGs). The prognostic impact of HMEMRDEGs was determined, and enrichment analyses were performed on essential genes. A HMEMRDEGs-based risk score system was established using LASSO and multivariable Cox regression analyses. High- and low-risk patient groups were subjected to gene set variation, immune infiltration, and immunophenoscore analyses. A nomogram was established by combining the clinical features of patients with LIHC using a risk model.
Twenty-eight HMEMRDEGs were identified. A prognostic model based on five key HMEMRDEGs revealed distinct biological characteristics between high- and low-risk LIHC groups. Functional enrichment analyses showed that these genes were involved in glucose metabolism and cancer-related signaling pathways, including AMPK and PI3K/Akt/mTOR. GSVA and immune infiltration analyses demonstrated that the high-risk group was enriched in oncogenic pathways and exhibited a more immunosuppressive microenvironment. Additionally, the high-risk group had significantly lower immunophenoscores, suggesting reduced responsiveness to immunotherapy.
Our results demonstrate the profound impact of HMEMRDEGs on LIHC progression. We established a predictive risk model incorporating 5 key genes, which serves as a prognostic predictor in LIHC.
缺氧和线粒体功能障碍是肝细胞癌（LIHC）进展的关键因素。本研究旨在探讨缺氧和线粒体能量代谢相关差异表达基因（HMEMRDEGs）在LIHC预后中的作用。
通过将来自癌症基因组图谱（TCGA）数据集的TCGA-LIHC中的差异表达基因（DEGs）与缺氧相关基因（HRGs）和线粒体能量代谢相关基因（MEMRGs）相交，从LIHC队列中鉴定出HMEMRDEGs。确定HMEMRDEGs的预后影响，并对关键基因进行富集分析。使用LASSO和多变量Cox回归分析建立基于HMEMRDEGs的风险评分系统。对高风险和低风险患者组进行基因集变异、免疫浸润和免疫表型评分分析。通过使用风险模型结合LIHC患者的临床特征建立列线图。
鉴定出28个HMEMRDEGs。基于5个关键HMEMRDEGs的预后模型揭示了高风险和低风险LIHC组之间不同的生物学特征。功能富集分析表明，这些基因参与葡萄糖代谢和癌症相关信号通路，包括AMPK和PI3K/Akt/mTOR。基因集变异分析（GSVA）和免疫浸润分析表明，高风险组在致癌途径中富集，表现出更强的免疫抑制微环境。此外，高风险组的免疫表型评分显著较低，表明对免疫治疗的反应性降低。
我们的结果证明了HMEMRDEGs对LIHC进展的深远影响。我们建立了一个包含5个关键基因的预测风险模型，可作为LIHC的预后预测指标。
