Identification and verification of the effect of ferroptosis risk genes on gastric cancer cells and ferroptosis-related immune landscape analysis

Abstract

Abstract Gastric cancer is a highly prevalent tumour globally, and the prognosis after treatment is generally poor. Ferroptosis is a regulated type of programmed cell death that plays an important role in several cellular functions. This study utilised differentially expressed genes that were related to ferroptosis in gastric cancer for molecular subtyping. The genes of interest were acquired using WGCNA, and thereafter, the LASSO algorithm was employed to construct a risk prognostic model for ferroptosis-related genes(FRGs). We validated this model using PCA, ROC and other methods. We subsequently analysed immune cell infiltration amongst different ferroptosis-related risk score(FRRS) groups, and found that the high-FRRS group exhibited a markedly enhanced level of macrophage M2 content. Finally, ASCL2 was selected as the study object to validate the prognostic model of ferroptosis-related risk gene(FRRG) by screening the mutation status. The experimental results demonstrated that inhibiting ASCL2 expression in vitro resulted in a significant reduction of glutathione levels, accumulation of intracellular divalent iron ions, and mitochondrial morphological condensation and membrane thickening. In vivo, inhibition of ASCL2 expression inhibited gastric cancer cell growth and led to a significant reduction in intra-tumour glutathione. Validation and experimentation confirm that FRRS can serve as an independent prognostic factor, enabling risk stratification of patients, and that FRRGs have the potential to be used as therapeutic targets through inducing ferroptosis in cancer cells.