Ferroptosis-Related Genes Are Potential Therapeutic Targets and the Model of These Genes Influences Overall Survival of NSCLC Patients

Abstract

Background: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSCC) are two of the most common subtypes of non-small cell lung cancer (NSCLC), with high mortality rates and rising incidence worldwide. Ferroptosis is a mode of programmed cell death caused by lipid peroxidation, the accumulation of reactive oxygen species, and is dependent on iron. The recent discovery of ferroptosis has provided new insights into tumor development, and the clinical relevance of ferroptosis for tumor therapy is being increasingly appreciated. However, its role in NSCLC remains to be explored. Methods: The clinical and molecular data for 1727 LUAD and LUSCC patients and 73 control individuals were obtained from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. Gene expression profiles, copy number variations and somatic mutations of 57 ferroptosis-related genes in 1727 tumor samples from the four datasets were used in a univariate Cox analysis and consensus clustering analysis. The biological signatures of each pattern were identified. A ferroptosis score was generated by combining the univariate Cox regression analysis and random forest algorithm followed by principal component analysis (PCA) and further investigated for its predictive and therapeutic value in LUAD and LUSCC. Results: The expression of 57 ferroptosis-related genes in NSCLC patients differed significantly from that of normal subjects. Based on unsupervised clustering of ferroptosis-related genes, we divided all patients into three ferroptosis expression pattern groups, which showed differences in ferroptosis-associated gene expression patterns, immune cell infiltration levels, prognostic characteristics and enriched pathways. Using the differentially expressed genes in the three ferroptosis expression patterns, a set of 17 ferroptosis-related gene prognostic models was established, which clustered all patients in the cohort into a low score group and a high score group, with marked differences in prognosis (p < 0.001). The high ferroptosis score was significantly associated with positive response to radiotherapy (p < 0.001), high T stage (p < 0.001), high N stage (p < 0.001) and high-grade tumor (p < 0.001) characteristics. Conclusions: The 17 ferroptosis-associated genes show great potential for stratifying LUAD and LUSCC patients into high and low risk groups. Interestingly, a high ferroptosis score in LUAD patients was associated with a good prognosis, whereas a similar high ferroptosis score in LUSCC patients was associated with a poor prognosis. Familiarity with the mechanisms underlying ferroptosis and its implications for the treatment of NSCLC, as well as its effect on OS and PFS, may provide guidance and insights in developing new therapeutic targets for NSCLC.

METTL3-mediated m6A modification enhances ZDHHC16 expression in nonsmall- cell lung cancer patients, attenuating ferroptosis by suppressing CREB ubiquitination

“…Numerous studies have shown that ferroptosis is associated with various human diseases, including cancer, neurodegenerative diseases, ischemic reperfusion injury, and renal degeneration [28,29]. The glutathione peroxidase 4 (GPX4) pathway plays a central role in regulating ferroptosis, as evidenced by the cysteine/glutamate reverse transporter system X [30,31]. In this study, the ZDHHC16 gene reduced ferroptosis of NSCLC by the rehabilitation of mitochondrial structure.…”

Epigallocatechin gallate modulates ferroptosis through downregulation of tsRNA-13502 in non-small cell lung cancer

“…EGCG is considered the most abundant compound in green tea and is effective in treating several diseases, including NSCLC [ 27 ]. Ferroptosis, a novel form of regulated cell death, has emerged as an attractive therapeutic target in cancer, including NSCLC [ 28 , 29 ].…”

STARD12/14 are diagnostic and prognostic biomarkers of lung adenocarcinoma associated with epigenetic regulation, immune infiltration and ferroptosis

“…Ferroptosis refers to an iron dependent oxidative form of regulated cell death and plays dual roles in tumorigenesis by modulating tumor microenvironment and tumor immunity [61]. The expression pattern, prognostic value and mechanistic analysis of ferroptosis related genes have been initially explored in LUAD [62][63][64]. In our study, iron death was more closely linked to the protective role of STARD12, which may participate in the regulation of nine ferroptosis associated genes including ALOX15, DPP4, GLS2, NCOA4, ATP5MC3, CARS1, CISD1, FANCD2 and SLC7A1 to suppress tumor progression of LUAD.…”