Exploring a ferroptosis and oxidative stress-based prognostic model for clear cell renal cell carcinoma

Abstract

BackgroundFerroptosis is a newly defined cell death process triggered by increased iron load and tremendous lipid reactive oxygen species (ROS). Oxidative stress-related ferroptosis is of great important to the occurrence and progression of clear cell renal cell carcinoma (ccRCC), which is particularly susceptibility to ferroptosis agonist. Therefore, exploring the molecular features of ferroptosis and oxidative stress might guide the clinical treatment and prognosis prediction for ccRCC patients.MethodsThe differentially expressed ferroptosis and oxidative stress-associated genes (FPTOSs) between normal renal and ccRCC tissues were identified based on The Cancer Genome Atlas (TCGA) database, and those with prognostic significances were applied to develop a prognostic model and a risk scoring system (FPTOS_score). The clinical parameter, miRNA regulation, tumor mutation burden (TMB), immune cell infiltration, immunotherapy response, and drug susceptibility between two FPTOS-based risk stratifications were determined.ResultsWe have identified 5 prognosis-associated FPTOSs (ACADSB, CDCA3, CHAC1, MYCN, and TFAP2A), and developed a reliable FPTOS_socre system to distinguish patients into low- and high-risk groups. The findings implied that patients from the high-risk group performed poor prognoses, even after stratified analysis of various clinical parameters. A total of 30 miRNA-FPTOS regulatory pairs were recognized to identify the possible molecular mechanisms. Meanwhile, patients from the high-risk group exhibited higher TMB levels than those from the low-risk groups, and the predominant mutated driver genes were VHL, PBRM1 and TTN in both groups. The main infiltrating immune cells of high- and low-risk groups were CD8+ T cells and resting mast cells, respectively, and patients from the high-risk groups showed preferable drug responsiveness to anti-PD-1 immunotherapy. Eventually, potential sensitive drugs (cisplatin, BI-D1870, and docetaxel) and their enrichment pathways were identified to guide the treatment of ccRCC patients with high-risk.ConclusionOur study comprehensively analyzed the expression profiles of FPTOSs and constructed a scoring system with considerable prognostic value, which would supply novel insights into the personalized treatment strategies and prognostic evaluation of ccRCC patient.

Identification and validation of m6A‐associated ferroptosis genes in renal clear cell carcinoma

“…CHAC1 (ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1) was found to be an endoplasmic reticulum inducer gene involved in degrading glutathione and promotes apoptosis or ferroptosis . CHAC1 is also an iron death-related gene that induces cell death in ccRCC cells and is one of the predictive biomarkers of ccRCC (Hong et al, 2021), and it was significantly correlated with the expression signatures of various immune cells (memory B cells, NK cells) (Lin et al, 2023).…”

“…Finally, we predicted potential drugs for the treatment of ccRCC based on prognosis-associated genes in ccRCC like AVELUMAB (Serzan & Atkins, 2021), DOCETAXEL (Lin et al, 2023). These drugs may be significantly impact the prognosis of ccRCC and provide a theoretical basis for treatment.…”

Glutathione‑degrading enzymes in the complex landscape of tumors (Review)

“…In evaluating patients with primary breast cancer, including ChaC1 mRNA expression levels in the scoring model led to changes in chemotherapy decisions in 16% of patients ( 152 ). In addition, ChaC1 has been included in prognostic models of renal cell carcinoma ( 153 ) and glioblastoma ( 154 ). Including ChaC1 in tumor prognosis predictions may guide personalized treatment options.…”