Disulfidptosis: new insights into cancer cell death and therapeutic targets

Scientists are taking a closer look at one of the most unusual forms of cell death ever described, a process known as disulfidptosis, which appears capable of destroying cancer cells while leaving healthy tissue largely unharmed. A new review published in the journal Medical Oncology by Zhenlong Zhou of Heilongjiang University of Chinese Medicine and Haichun Zhou of the Fourth Affiliated Hospital of Heilongjiang University of Chinese Medicine brings together the rapidly expanding body of knowledge on this emerging phenomenon, mapping the molecular machinery that drives it and assessing its promise as a foundation for low-toxicity anticancer therapy.

Disulfidptosis belongs to the growing family of programmed cell death modalities, which already includes apoptosis, necroptosis, pyroptosis, ferroptosis and cuproptosis. What sets it apart is its peculiar trigger and its equally peculiar execution mechanism. Rather than being launched by genetic damage, immune signaling or lipid peroxidation, disulfidptosis arises when a cancer cell suffers a catastrophic metabolic and redox imbalance, one that culminates in the irreversible collapse of the actin cytoskeleton, the internal scaffold that gives the cell its shape and motility. In the simplest terms, the cell’s skeleton literally disintegrates under the strain of accumulated disulfide bonds, and the cell dies.

At the heart of the process lies what the authors describe as the SLC7A11-cystine-NADPH-actin axis. SLC7A11, also known as xCT, is a cystine/glutamate antiporter that many cancer cells upregulate to import cystine, the oxidized dimer of cysteine, which they then reduce to cysteine for the synthesis of glutathione and other antioxidant molecules. This import strategy works well for tumor cells as long as they have abundant glucose, because glucose feeds the pentose phosphate pathway, which generates NADPH, the reducing power needed to convert incoming cystine back into cysteine. The transporter, in other words, is a double-edged sword: it equips cancer cells to withstand oxidative stress, but it creates a hidden dependency on a continuous supply of NADPH.

The vulnerability is exposed when glucose runs out. Under glucose starvation, NADPH production collapses, and the cystine that continues to flood into the cell through SLC7A11 can no longer be reduced. Abnormal levels of intracellular cystine and other disulfide molecules accumulate, and aberrant disulfide bonds begin to form between cysteine residues on a broad range of proteins. Previous work by Liu and colleagues, published in Nature Cell Biology in 2023, demonstrated that the actin cytoskeleton is particularly susceptible to this disulfide stress. When excessive disulfide bonding disrupts actin networks, the cytoskeleton collapses, cells detach from their surroundings, shrink and die. This actin-centered death is the defining hallmark of disulfidptosis.

The review also emphasizes why certain cancer cells are unusually susceptible to this death route. Tumors are metabolically rewired cells, and many of them, including those with high SLC7A11 expression, exist in a state the authors call a fragile redox equilibrium, balancing heavy cystine import against tight NADPH budgets. Notably, cells that have evolved resistance to apoptosis or to ferroptosis, the iron-dependent lipid peroxidation death, often show heightened vulnerability to disulfidptosis, suggesting that this pathway could be exploited against tumors that have outmaneuvered conventional therapies. This synthetic-lethal logic, where a second stress is applied to cells already carrying a metabolic liability, underlies much of the enthusiasm surrounding the field.

Regulation of disulfidptosis is a multi-layered affair, spanning metabolic, redox and signaling networks. On the metabolic side, glucose uptake through transporters such as GLUT1 and GLUT3, glycolytic flux, and activity of the pentose phosphate pathway enzymes glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase all determine how much NADPH a cell can muster. The review highlights that cancer cells can draw NADPH from alternative sources, including lactate and glutamine metabolism, when glucose is scarce, which complicates therapeutic strategies based purely on glucose deprivation. On the redox side, the glutathione system, comprising glutathione, glutathione peroxidases and glutathione reductase, and the thioredoxin system, comprising thioredoxin, thioredoxin reductase and related proteins such as TRP14, act as buffers against disulfide stress. Inhibiting thioredoxin reductase 1, for example, has been shown to sensitize glucose-starved glioblastoma cells to disulfidptosis, as reported by Tang and colleagues in Cell Death and Differentiation in 2025.

Several key signaling pathways tune this machinery. The Keap1-Nrf2 pathway, the master sensor of oxidative and electrophilic stress, regulates the expression of SLC7A11 and a suite of antioxidant genes, and its frequent activation in tumors, through Keap1 mutations or NRF2 stabilization, can either protect cells from disulfide stress or, paradoxically, load them with more cystine import capacity that becomes lethal when energy fails. The AMPK pathway, activated under energy stress through LKB1 and other sensors, helps cells conserve NADPH and survive glucose starvation; cells with LKB1 mutations, such as a subset of non-small cell lung cancers, are consequently more likely to die by disulfidptosis when deprived of glucose. The tumor suppressor p53 adds another layer of complexity, shaping glucose metabolism and redox gene expression in ways that can either sensitize or protect cells depending on context.

The review also details the cytoskeletal components that serve as executioners of the process. Rac1, a small GTPase that governs actin polymerization, activates the WAVE regulatory complex, which includes NCKAP1 and the Arp2/3-activating machinery that drives branched actin network formation. Disulfide stress-induced aberrant bonding among actin and its interacting proteins cripples these structures, and studies have shown that manipulating Rac1-WAVE signaling alters sensitivity to disulfidptosis. Because many of these same proteins also drive cancer cell migration, invasion and metastasis, the actin cytoskeleton represents a doubly attractive target: disrupting it kills vulnerable tumor cells and simultaneously undermines their ability to spread.

Importantly, the authors caution that the story is not uniformly favorable. Functional polarity reversal of core regulatory molecules, in which a factor that normally promotes disulfidptosis in one context protects against it in another, and the profound heterogeneity of tumors can both blunt therapeutic efficacy. Some tumors with low SLC7A11 expression may be resistant, while others compensate through alternative NADPH-generating routes. This heterogeneity is one of the principal bottlenecks the field must overcome, alongside a shortage of highly specific pharmacological tools to induce or inhibit disulfidptosis selectively.

Despite these challenges, early translational efforts are encouraging. Researchers have developed nanoinducers, including copper-based nanoparticles and FTO-targeting nanodrugs, that promote disulfidptosis while simultaneously remodeling the immunosuppressive tumor microenvironment, thereby boosting immunotherapy. Sonodynamic nanoparticles carrying GLUT1 inhibitors and cystine-containing polymers have been tested in bladder cancer models. Combination strategies pairing disulfidptosis induction with ferroptosis, cuproptosis or pyroptosis, or with agents that inhibit DNA repair and force cell cycle arrest, are being explored to enhance tumor killing. The review argues that the selectivity of disulfidptosis for metabolically vulnerable cancer cells, which spares normal cells that lack the same cystine-import dependence, offers a route toward therapies with a wider therapeutic window than conventional cytotoxic chemotherapy.

Looking forward, the authors call for precise molecular classification systems that identify which tumors carry the disulfidptosis-susceptible phenotype, development of targeted drugs against the SLC7A11-NADPH-actin axis, and exploration of synergistic strategies combining metabolic interventions with immunotherapy. If those goals can be met, disulfidptosis may move from a laboratory curiosity to a genuine clinical option, giving oncologists a way to exploit the very metabolic addictions that cancer cells rely on for survival. For now, the field stands at an inflection point, with the fundamental biology largely mapped and the first-generation tools beginning to emerge, and the coming years will determine whether the actin cytoskeleton, that ancient structural scaffold of the cell, becomes the next great target in cancer medicine.