Disulfidptosis Inhibitors
Disulfidptosis is a recently identified form of regulated cell death that is distinct from apoptosis, ferroptosis, and other known cell death pathways. It is characterized by the accumulation of intracellular disulfides, particularly cystine, which leads to severe disulfide stress and the subsequent collapse of the actin cytoskeleton. This process is most prominently observed in cancer cells that overexpress the cystine/glutamate antiporter SLC7A11 (also known as xCT). While SLC7A11 is typically associated with protecting cells from ferroptosis by providing cysteine for glutathione synthesis, it becomes a liability under conditions of glucose starvation. In the absence of sufficient glucose, cells cannot generate enough NADPH via the pentose phosphate pathway to reduce the imported cystine into cysteine. The resulting accumulation of cystine and other disulfides triggers the formation of aberrant intermolecular disulfide bonds among actin cytoskeleton proteins, such as profilin-1 and various myosins, leading to cytoskeleton contraction, plasma membrane detachment, and rapid cell death.
The discovery of Disulfidptosis has significant implications for cancer therapy, especially for tumors that are highly dependent on SLC7A11, such as certain types of lung, breast, and kidney cancers. These 'SLC7A11-high' tumors are often resistant to ferroptosis-inducing agents but are uniquely vulnerable to disulfidptosis when glucose metabolism is impaired. This provides a therapeutic window to selectively target these aggressive cancers by exploiting their metabolic inflexibility. Beyond oncology, the role of disulfidptosis in other diseases involving oxidative stress and metabolic dysfunction is an active area of investigation. Inhibitors of disulfidptosis are currently being used as research tools to dissect the molecular mechanisms of this pathway and to explore its therapeutic potential. These inhibitors can be broadly classified into three categories.
The first includes thiol-containing antioxidants, such as N-acetylcysteine (NAC) and 2-mercaptoethanol, which can directly reduce the accumulated disulfides and prevent the collapse of the actin cytoskeleton. The second category consists of glucose or other metabolic substrates that can restore NADPH levels, thereby maintaining the cell's reductive capacity. The third category involves inhibitors of the actin cytoskeleton remodeling process, which can delay or prevent the physical collapse of the cell. Current research progress is focused on identifying the specific proteins within the actin cytoskeleton that are most sensitive to disulfide bond formation and on developing small molecules that can either induce or inhibit this process. A major challenge in the field is the dual role of SLC7A11 in ferroptosis and disulfidptosis; treatments must be carefully designed to avoid unintentionally protecting cells from one form of death while trying to induce another. Future research will likely explore combination therapies that pair SLC7A11-targeted agents with glucose transporters (GLUT) inhibitors or other metabolic modulators to maximize the induction of disulfidptosis in tumor cells.
Understanding the crosstalk between disulfidptosis and other cell death pathways will be crucial for developing effective and safe clinical interventions. This emerging field promises to redefine our approach to metabolic vulnerabilities in cancer.
