Cellular Membrane Protein GRINA is Highly Expressed and Associated with Survival Outcomes in Liver Cancer Patients

Abstract

Objective

Hepatocellular carcinoma (HCC), a lethal cancer with high global mortality, may be targeted through ferroptosis, an iron-dependent form of cell death. Despite its potential, the prognostic value of ferroptosis in HCC is underexplored.

Methods

Our study leveraged single-cell and bulk sequencing datasets to identify ferroptosis-related genes and developed a prognostic model via Cox and LASSO regression analyses. Survival and mutation analyses led to the creation of a nomogram for predicting patient prognosis. Furthermore, we investigated the role of GRINA, a ferroptosis-related gene, through functional assays, including cell proliferation, colony formation, and metastatic potential analyses. We also assessed mitochondrial abnormalities, intracellular iron, and ROS levels in GRINA-knockdown cells.

Results

The developed ferroptosis-related model classified HCC patients into risk groups, revealing notable survival disparities. High-risk patients presented increased immune checkpoint gene expression. The nomogram revealed robust prognostic accuracy. Additionally, we found that GRINA suppression reduced HCC cell proliferation, colony formation, and metastatic potential. Cells with GRINA knockdown presented mitochondrial abnormalities and increased intracellular iron and ROS levels.

Conclusions

By analysing multiomics sequencing data, we established a connection between ferroptosis-related risk groups and the tumor immune microenvironment. These findings provide novel insights into the role of ferroptosis in HCC and suggest that GRINAinhibition is a potential therapeutic strategy, leading to mitochondrial damage and the induction of ferroptosis in HCC cell lines.

Keywords

Hepatocellular carcinoma / Ferroptosis / Prognostic signature / Nomogram / GRINA

3Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Air Force Medical University, Xi’an 710032, China

© The Author(s), under exclusive licence to Huazhong University of Science and Technology 2025

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s11596-025-00025-3.

Funding This research was supported by the National Natural Science Foundation of China (No. 82102512).

Availability of Data and Materials The research analysis was conducted using data from publicly available repositories, specifically the TCGA- LIHC database, along with the GSE189903 and GSE14520 datasets from the GEO database.

Declarations

Conflict of Interest The authors confirm that they have no known competing interests.

Ethics Approval and Consent to Participate Human subjects research was approved by the Ethics Committee of Xijing Hospital, part of the Air Force Medical University. Local regulatory standards and the hospital protocol were strictly adhered to throughout the study. Written informed consent was obtained from all participants prior to their inclusion in the research activities. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Xijing Hospital, part of the Air Force Medical University. All procedures involving human participants were performed in compliance with local regulatory standards and institutional protocols.

Consent for Publication Not applicable.

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