Disulfidptosis: a new form of programmed cell death

Abstract

Disulfidptosis, a new form of cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to the intracellular accumulation of disulfides. This discovery will eventually aid in the development of therapeutic strategies against cancer.

Fig. 1

Schematic overview of the main difference between apoptosis and disulfidptosis under glucose starvation or blockade of glucose uptake in SLC7A11^low and SLC7A11^high cells. In SLC7A11^low cells, intracellular glucose level, formation of G6P, and formation of NADPH and pyruvate via the PPP and glycolysis, respectively, decreased under conditions of glucose starvation or blockade of glucose uptake. The formation of pyruvate through the TCA cycle and mitochondrial oxidative phosphorylation were inhibited. These changes up-regulated the expression of Bax and Bak, led to the release of cytochrome c from mitochondria, activated Casp-3, and promoted PARP-induced membrane blebbing and cell apoptosis. In SLC7A11^high cells, glucose starvation or blockade of glucose uptake led to high uptake of cystine and reduction to cysteine, NADPH depletion, disulfide stress caused by the intracellular accumulation of disulfides, which activated the Rac–WRC-Arp2/3 signaling pathway, contributing to aberrant disulfide bonds in actin cytoskeleton proteins and disulfidptosis. The red fonts indicate inhibition or reduction, and the black fonts indicates promotion or increase. Abbreviations: GLU, glucose; HK, hexokinase; PPP, pentose phosphate pathway; G6P, glucose-6-phosphate; R5P, ribulose-5-phosphate; Cyto c, cytochrome c; TCA, tricarboxylic acid; Bax, Bcl-2-associated X protein; BAK, BCL2 antagonist; NADPH, nicotinamide adenine dinucleotide phosphate; Casp-3, caspase-3; PARP, poly (ADP-ribose) polymerase; WRC, WAVE regulatory complex; Apr, actin-related protein