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Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma.

ABSTRACT: Ferroptosis is a novel process of regulated cell death discovered in recent years, mainly caused by intracellular lipid peroxidation. It is morphologically manifested as shrinking of mitochondria, swelling of cytoplasm and organelles, rupture of plasma membrane, and formation of double-membrane vesicles. Work done in the past 5 years indicates that induction of ferroptosis is a promising strategy in the treatment of hepatocellular carcinoma (HCC). System xc ^- /GSH/GPX4, iron metabolism, p53 and lipid peroxidation pathways are the main focus areas in ferroptosis research. In this paper, we analyze the ferroptosis-inducing drugs and experimental agents that have been used in the last 5 years in the treatment of HCC. We summarize four different key molecular mechanisms that induce ferroptosis, i.e., system xc ^- /GSH/GPX4, iron metabolism, p53 and lipid peroxidation. Finally, we outline the prognostic analysis associated with ferroptosis in HCC. The findings summarized suggest that ferroptosis induction can serve as a promising new therapeutic approach for HCC and can provide a basis for clinical diagnosis and prevention of this disease.

SUBMITTER: Li L

PROVIDER: S-EPMC9424770 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma.

Li Lanqing L Wang Xiaoqiang X Xu Haiying H Liu Xianqiong X Xu Kang K

Frontiers in molecular biosciences 20220816

Ferroptosis is a novel process of regulated cell death discovered in recent years, mainly caused by intracellular lipid peroxidation. It is morphologically manifested as shrinking of mitochondria, swelling of cytoplasm and organelles, rupture of plasma membrane, and formation of double-membrane vesicles. Work done in the past 5 years indicates that induction of ferroptosis is a promising strategy in the treatment of hepatocellular carcinoma (HCC). System xc - /GSH/GPX ...[more]

PMID: 36052168

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Project description:PurposeFerroptosis, as a novel regulated cell death form, has a close interaction with metabolism, which is largely unknown in cancer. In the present study, we conducted a comprehensive analysis of ferroptosis-related metabolic genes to delineate the metabolic signatures induced by ferroptosis and evaluate its prognostic significance in hepatocellular carcinoma (HCC).MethodsThe ferroptosis-related metabolic genes (Fer-MRGs) were identified by correlation analyses with transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Then, univariate and the least absolute shrinkage and selection operator Cox regression analysis was used to establish a novel risk score model. Univariate and multivariate COX analyses were used to identify independent prognostic factors for overall survival (OS) of HCC, and a nomogram was developed. The Fer-MRGs' expression was further evaluated by quantitative real-time polymerase chain reaction in HCC.ResultsA total of 77 metabolic genes were identified as Fer-MRGs, and 26 were found with prognostic values for OS of HCC. Then, a novel nine-gene (AKR1C3, ATIC, G6PD, GMPS, GNPDA1, IMPDH1, PRIM1, RRM2, and TXNRD1) risk score model was constructed. Survival analyses showed worse OS in high-risk patients both in the training and validation groups. The model was also identified as an independent prognostic factor for HCC, and a prognostic nomogram for OS was further established with superior discriminative capacity and prediction accuracy. Notably, close correlations were also identified between the risk score and the expression of immune checkpoint genes, immune subtypes of tumor, and susceptibility of HCC to chemotherapeutic agents. Finally, elevated expression of eight Fer-MRGs (except for IMPDH1) was further verified in 16 pairs of HCC tumor and adjacent tissues.ConclusionThese results indicated the intense interaction between ferroptosis and metabolism, the significant role of ferroptosis-related MRGs, and the great potential of the novel risk score model for prognosis prediction in HCC.

Project description:BackgroundUnderstanding the interplay between disulfidptosis, ferroptosis, and hepatocellular carcinoma (HCC) could provide valuable insights into the pathogenesis of HCC and potentially identify novel therapeutic targets for the treatment of this deadly disease. This study aimed to identify a prognostic signature for HCC by examining the differential expression of genes related to disulfidptosis and ferroptosis (DRG-FRG), and to assess its clinical applicability.MethodsBy integrating 23 disulfidptosis and 259 ferroptosis related genes with HCC messenger RNA (mRNA) expression data from The Cancer Genome Atlas (TCGA), differentially expressed DRG-FRG genes were identified. From these, 11 DRG-FRG genes were selected to construct a risk signature model using least absolute shrinkage and selection operator regression analyses. The prognostic performance of this model was evaluated by Kaplan-Meier survival analysis and time-dependent receiver operating characteristic (ROC) analysis. Subsequently, a nomogram was built by combining the signature with clinical variables. To further delve into the underlying mechanisms, we performed bioinformatics analysis using a variety of databases.ResultsA prognostic signature based on 11 DRG-FRG genes effectively categorized HCC patients into high- and low-risk groups, showing a significant survival difference. Even after considering clinical variables, this signature remained an independent prognostic factor. Furthermore, the signature played a role in various critical biological processes and pathways that drive HCC progression. Potential therapeutic benefits could be derived from small molecule drugs targeting NQO1 and SLC7A11. Interestingly, the high-risk group exhibited resistance to several chemotherapeutic drugs, yet showed sensitivity to others when contrasted with the low-risk group. Lastly, the DRG-FRG genes signature had a strong correlation with the tumor immune microenvironment, marked by an elevated expression of immune checkpoint molecules in the high-risk group.ConclusionsThe signature based on 11 DRG-FRG genes stands out as a promising prognostic biomarker for HCC. Beyond its predictive value, it sheds light on the intricate crosstalk between DRG-FRG genes and HCC. Importantly, these findings could pave the way for enhanced prognostic prediction, informed treatment decisions, and the advancement of immunotherapy for HCC patients.

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Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma.

Publications

Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma.

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