Disulfidptosis: a new target for metabolic cancer therapy

Abstract

Altered metabolism is a hallmark of cancer and presents a vulnerability that can be exploited in cancer treatment. Regulated cell death (RCD) plays a crucial role in cancer metabolic therapy. A recent study has identified a new metabolic-related RCD known as disulfidptosis. Preclinical findings suggest that metabolic therapy using glucose transporter (GLUT) inhibitors can trigger disulfidptosis and inhibit cancer growth. In this review, we summarize the specific mechanisms underlying disulfidptosis and outline potential future research directions. We also discuss the challenges that may arise in the clinical translation of disulfidptosis research.

Fig. 1

Schematic diagram of the mechanism of disulfidptosis a) The key to the occurrence of disulfidptosis is the disulfide stress caused by the accumulation of disulfides such as cystine. The reasons for the accumulation of disulfides include the high expression of SLC7A11 or the excessive intake of cystine caused by environmental homocysteine and the blockage of the reduction of cystine in the cell. Reduction of cystine requires NADPH. When intracellular NADPH is sufficient, excess cystine will be converted into cysteine, which will avoid the production of disulfide stress. The depletion of NADPH occurred before the production of disulfide stress, and NADPH is mainly the product of glucose PPP pathway metabolism. Starvation or the use of GLUT inhibitors will result in reduced glucose supply and thus NADPH supply. In addition, excess cystine also contributes to the depletion of NADPH. Afterward, under the pressure of disulfide stress, the formation of disulfide bonds between actin cytoskeleton proteins and the collapse of the F-actin network will occur, eventually triggering disulfidptosis. Among them, the collapse of the F-actin network involves F-actin contracts and detaches from the plasma membrane, while disulfidptosis is related to Rac–WRC-mediated lamellipodia formation. b) Intracellular NADPH is depleted by glucose starvation, GLUT inhibitors, or by providing excess cystine. This will trigger the production of disulfide stress in the cell, leading to the formation of disulfide bonds between actin cytoskeleton proteins and the collapse of the F-actin network, eventually triggering disulfidptosis. GADPH: Glyceraldehyde-3-phosphate dehydrogenase, GLUT: Glucose transporter, PPP: Pentose phosphate pathway, R5P: Ribose 5-phosphate, SLC7A11: Solute carrier family 7 member 11, WRC: WAVE regulatory complex