Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency and cystine import via solute carrier family 7 member 11.

Chromophobe (Ch) renal cell carcinoma (RCC) arises from the intercalated cell in the distal nephron. There are no proven treatments for metastatic ChRCC. A distinguishing characteristic of ChRCC is strikingly high levels of reduced (GSH) and oxidized (GSSG) glutathione. Here, we demonstrate that ChRCC-derived cells exhibit higher sensitivity to ferroptotic inducers compared with clear-cell RCC. ChRCC-derived cells are critically dependent on cystine via the cystine/glutamate antiporter xCT to maintain high levels of glutathione, making them sensitive to inhibitors of cystine uptake and cyst(e)inase. Gamma-glutamyl transferase 1 (GGT1), a key enzyme in glutathione homeostasis, is markedly suppressed in ChRCC relative to normal kidney. Importantly, GGT1 overexpression inhibits the proliferation of ChRCC cells in vitro and in vivo, suppresses cystine uptake, and decreases levels of GSH and GSSG. Collectively, these data identify ferroptosis as a metabolic vulnerability in ChRCC, providing a potential avenue for targeted therapy for these distinctive tumors.

Blood glutathione and cysteine changes in cardiovascular disease.

The need to investigate aminothiols such as glutathione (GSH), cysteine (Cys), and homocysteine (Hcy) in blood is stimulated by the current interest in hyperhomocysteinemia as a risk factor for atherosclerosis. Our current goal was to determine whether various cardiovascular (CV) diseases altered levels of GSH and Cys in blood and the relationships between these two thiols. Blood samples from 96 patients with atherosclerosis and other CV diseases were analyzed and compared with those from 33 control subjects. In CV patients, GSH levels were normal, but free plasma Cys was significantly higher (P < .0001). In patients with atherosclerosis, bound plasma Cys was 21% higher than that in control subjects (P < .0001), and in patients with other CV diseases it was 14% higher (P = .023). Also, in patients with CV diseases, correlations of free GSH with free Cys (P < .007) and total GSH and Cys with age (P < .04) differed from that in control subjects. There were no differences related to functional disability or duration of disease. A key finding was that these abnormal levels of plasma Cys occurred in both atherosclerotic and non-atherosclerotic CV diseases. These results indicate that high levels of oxidized and bound Cys in CV patients create an oxidative environment that may increase susceptibility to vascular damage.