Table 1.
Summary of the three renal cell carcinoma (RCC) subtypes, incidences, main mutations, and GSH regulation.
| RCC Subtypes | Clear Cell | Papillary | Chromophobe |
|---|---|---|---|
| Incidence | 75% | 15% | 5% |
| Main mutations | VHL | MET, FH | TP53, PTEN |
| Metabolites | GSH, GSSG increased | GSH, GSSG increased | GSH, GSSG increased |
| GSH regulation | 1. GCL protein abundance increases; 2. Increased serum GGT as a marker for metastatic ccRCC; 3. GLS1, glutamine importers, and cysteine antiporter xCT enhance to favor GSH synthesis; 4. Increased PPP flux to produce NADPH for GSH conversion. |
1. FH mutation causes HIF stabilization; 2. FH mutation activates NRF2–ARE pathway, leading to increased GSH synthesis and enhanced expression of antioxidant proteins. |
Loss of GGT1 increases sensitivity to oxidative stress in chRCC cells. |
ccRCC: clear cell RCC; chRCC: chromophobe RCC; pRCC: papillary RCC; VHL: von Hippel-Lindau; MET: proto-oncogene c-Met; FH: fumarate hydrotase; TP53: tumor antigen p53; PTEN: phosphatase and tensin homolog; PPP: pentose phosphate pathway; HIF: hypoxia-inducible factor; NRF2: nuclear factor erythroid 2-related factor 2; ARE: antioxidant response element; GGT1: γ-glutamyl transferase 1.