Upregulation of Metallothionein 1 G (MT1G) Negatively Regulates Ferroptosis in Clear Cell Renal Cell Carcinoma by Reducing Glutathione Consumption

Ferroptosis is characterized by lipid peroxidation and iron accumulation, closely associated with clear cell renal cell carcinoma (ccRCC). It is of great significance for prognostic prediction and treatment of ccRCC to find biomarkers related to ferroptosis. We conducted several bioinformatic analyses using the transcriptome data and clinical information derived from online databases. Firstly, we identified the differentially expressed target genes in ccRCC. Then, t test and COX analysis were used to determine whether it was an independent prognostic factor combined with clinical information. String and gene set enrichment analysis (GSEA) were used to predict its function. Finally, we used ccRCC cells: 769-P and KAKI-1 in vitro to verify the regulation of target genes on cell proliferation apoptosis, iron metabolism, and GSH metabolism, which were used to judge the effect of target genes on ferroptosis. The study showed that MT1G is downregulated in ccRCC tissues compared with normal renal tissues. However, the ccRCC patients with higher expression relatively had higher malignancy and advanced stages. MT1G is an independent adverse factor for the prognosis of ccRCC. The protein interaction network analysis and GSEA showed that MT1G was closely related to GSH metabolism-related proteins (GSR) and lipid oxidation-related proteins (PLA2G2A). Samples with high expression of MT1G were enriched in "glutathione metabolism," "oxidative phosphorylation," and "proteasome," whose function was involved in GSH metabolism and lipid peroxidation. The term associated with the occurrence and development of tumors included "P53 signaling pathway." Furthermore, in vitro experiments showed that MT1G partially blocked ferroptosis induced by erastin and sorafenib-induced ccRCC cell lines (769-P and CAKI-1). The mechanism may be that MT1G affects ferroptosis by regulating GSH consumption in ccRCC cells. MT1G may be a negative regulator of ferroptosis in ccRCC cells and a biomarker of poor prognosis.

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