Prognostic Role and Potential Mechanisms of the Ferroptosis-Related Metabolic Gene Signature in Hepatocellular Carcinoma

Abstract

Purpose Ferroptosis, 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). Methods The 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. Results A 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. Conclusion These 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.

Effect of Supplementation With Selenium-Yeast on Muscle Antioxidant Activity, Meat Quality, Fatty Acids and Amino Acids in Goats

“…When the body is in a state of OS, it may participate in the AA metabolic process because ROS can also oxidize blood and structural proteins and inhibit the proteolytic system (54). Dai et al (55) showed that cysteine limitation reduces the biosynthesis of glutathione (GSH) and causes the depletion of GSH, which directly inhibits the activity and stability of GPX4. In addition, cystathionine, cysteine and glycine are important precursors in the synthesis of GSH-Px, which has a rate-limiting role in the synthesis process (56).…”

All-trans retinoic acid inhibits the malignant behaviors of hepatocarcinoma cells by regulating ferroptosis

“… 21 More than 50% of patients with liver cancer have slight iron overload and more than 80% of ferroptosis-related genes are different between HCC and normal tissues; high expression of GPX4, G6PD, and NQO-1 have been reported to be closely related to poor prognosis. 22 , 23 In this study, we identified the DEGs between HCC samples and normal liver samples, from TCGA database and GSE36376 database, and found 53 of them to be related to ferroptosis, further indicating the important role of ferroptosis in HCC. Ferroptosis is closely regulated by intracellular signaling pathways, including amino acid metabolism, lipid metabolism, and iron ion metabolism.…”

Identification of a nucleotide metabolism-related signature to predict prognosis and guide patient care in hepatocellular carcinoma

“…Numerous prognostic models for hepatocellular carcinoma have been reported previously. For example, ferroptosis-related and lipid metabolism-related prognostic model were established for prognostic analysis ( Hu et al, 2020 ; Dai et al, 2021 ). However, the prognostic model constructed by nucleotide metabolism-related genes has yet to be studied in depth.…”