Disulfidptosis, A Novel Cell Death Pathway: Molecular Landscape and Therapeutic Implications

Abstract

Programmed cell death is pivotal for several physiological processes, including immune defense. Further, it has been implicated in the pathogenesis of developmental disorders and the onset of numerous diseases. Multiple modes of programmed cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis, have been identified, each with their own unique characteristics and biological implications. In February 2023, Liu Xiaoguang and his team discovered "disulfidptosis," a novel pathway of programmed cell death. Their findings demonstrated that disulfidptosis is triggered in glucose-starved cells exhibiting high expression of a protein called SLC7A11. Furthermore, disulfidptosis is marked by a drastic imbalance in the NADPH/NADP+ ratio and the abnormal accumulation of disulfides like cystine. These changes ultimately lead to the destabilization of the F-actin network, causing cell death. Given that high SLC7A11 expression is a key feature of certain cancers, these findings indicate that disulfidptosis could serve as the basis of innovative anti-cancer therapies. Hence, this review delves into the discovery of disulfidptosis, its underlying molecular mechanisms and metabolic regulation, and its prospective applications in disease treatment.

Figure 1.

Mechanism of disulfidptosis. Under normal conditions, sufficient amounts of glucose are transported into the cell, and a large amount of NADPH is generated through the pentose phosphate pathway. This NADPH reduces the cystine transported by SLC7A11 into cysteine. Simultaneously, the intracellular reducing environment also prevents the formation of other disulfide bonds, thus protecting the cell from disulfide stress and ensuring cell survival. However, in cells undergoing disulfidptosis, conditions of glucose starvation or GLUT inhibition lead to reduced glucose uptake and diminished NADPH production, resulting in the collapse of the cellular redox environment. The consequent accumulation of intracellular cystine and other disulfides triggers disulfide stress. This leads to disulfide bond formation in actin filaments, collapse of the F-actin cytoskeleton, and ultimately induces cell death. Abbreviations: NADPH, nicotinamide adenine dinucleotide phosphate; G6PD, glucose-6-phosphate dehydrogenase; 6GPD, 6-phosphogluconate dehydrogenase; Cys, Cysteine.

Figure 2.

Structure and function of SLC7A11. (A) Extracellular cystine is taken into the cell through SLC7A11 and then transformed into cysteine by a reduction reaction that depletes NADPH. Following this, cysteine is converted into GSH in a two-step process. GPX4 employs GSH to reduce lipid hydroperoxides to lipid alcohols, with GSH being oxidized to GSSG. Subsequently, GSSG is reverted to GSH via a GR-mediated reduction, utilizing NADPH in the process. (B) Essential conditions for triggering disulfidptosis: glucose starvation/GLUT inhibition and overexpression of SLC7A11. Abbreviations: GPX4, glutathione peroxidase 4; GSH, reduced glutathione; GSSG, oxidized glutathione; LOOH, lipid hydroperoxide; LOH, lipid alcohol.

Figure 3.

Regulatory pathways of disulfidptosis. In SLC7A11-overexpressing cells, treatment with GLUT inhibitors causes intracellular cystine accumulation and NADPH consumption. Additionally, disulfide bonds between actin molecules are generated via the Rac/WRC/Arp2/3 pathway. This eventually results in cell death. Abbreviations: PPP, pentose phosphate pathway; R5P, ribulose-5-phosphate; NADPH, nicotinamide adenine dinucleotide phosphate; WRC, WAVE regulatory complex; Arp, actin-related protein.

Figure 4.

Relationship of sulfide metabolites with disulfidptosis and ferroptosis. Cysteine is a crucial intermediate product in intracellular sulfur metabolism. On one hand, cysteine is generated to produce hydrogen sulfide (H₂S) through the catalytic actions of cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), or via the pathway involving cysteine aminotransferase (CAT) and 3-mercaptopyruvate sulfurtransferase (3-MST). On the other hand, cysteine metabolism is intricately linked to processes such as disulfidptosis and ferroptosis: the accumulation of cystine contributes to disulfidptosis; while glutathione, synthesized from cysteine, can, under the influence of GPX4, reduce lipid hydroperoxides to lipid alcohols, thereby inhibiting ferroptosis. Abbreviations: GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, oxidized glutathione; LOH, Lipid Alcohols; LOOH, Lipid Hydroperoxides; NADPH, nicotinamide adenine dinucleotide phosphate; WRC, WAVE regulatory complex; Arp, actin-related protein; 3-MST, 3-mercaptopyruvate sulfurtransferase; CAT, cysteine aminotransferase; CBS, cystathionine-β-synthase; CSE, cystathionine g-lyase; DAO, D-amino acid oxidase.

Figure 5.

Composition of the WRC and the activity of the Rac1-WRC-Arp2/3 signaling pathway. WRC is a five-subunit complex, including the protein families: ABI (ABI1, ABI2, or ABI3), WAVE (WAVE1, WAVE2, or WAVE3), NCKAP1, CYFIP (CYFIP1 or CYFIP2), and HSPC300. In the absence of Rac1 binding, the WRC is in an inhibited state. Binding of Rac1 to CYFIP1 induces WRC activation, triggering the release of the WCA domain, thereby activating Arp2/3 and contracting F-actin. Abbreviations: Rac1, Ras-related C3 Botulinum Toxin Substrate 1; Arp2/3, Actin-related Protein 2/3; ABI, Abl-interactor; NCKAP1, NCK-associated protein 1; CYFIP1, Cytoplasmic FMR1-interacting protein 1; HSPC300, Hematopoietic stem/progenitor cell protein 300.