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. 2025 Jul 1.
doi: 10.1007/s10620-025-09185-7. Online ahead of print.

Roles of Hypoxia and Mitochondrial Energy Metabolism Related Genes in Predicting the Prognosis of Liver Hepatocellular Carcinoma

Miaolong He #  1 , Xiaole Wang #  2 , Xiaolei Xu #  3 , Xiaojuan Wang  1   4 , Xixin Wang  1 , Xiaobin Feng  5   6
Affiliations

Roles of Hypoxia and Mitochondrial Energy Metabolism Related Genes in Predicting the Prognosis of Liver Hepatocellular Carcinoma

Miaolong He et al. Dig Dis Sci. .

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: HMEMRDEGs; Immunity; Liver hepatocellular carcinoma; Prognosis; Risk score.

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Conflict of interest statement

Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: This is an observational study. The Ethics Committee of Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University has confirmed that no ethical approval is required. Consent to participate: Not applicable. Consent for publication: Not applicable.

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