Disulfidptosis: A Metabolic Cell Death Mechanism with Therapeutic Potential in Cancer

Disulfidptosis is a newly identified form of regulated cell death (RCD) first described in 2023, representing a significant advance in understanding programmed cell death pathways. This unique cell death modality is characterized by abnormal intracellular accumulation of disulfide bonds and disruption of redox homeostasis, leading to cytoskeletal collapse without caspase activation. Disulfidptosis is primarily triggered by glucose deprivation in cells with high expression of solute carrier family 7 member 11 (SLC7A11). Under these conditions, insufficient NADPH supply prevents the effective reduction of accumulated cystine to cysteine, thereby inducing disulfide stress. Distinct from apoptosis, ferroptosis, cuproptosis, or pyroptosis, disulfidptosis exhibits unique metabolic dependencies and a hallmark feature of cytoskeletal disintegration. Current evidence indicates that this mechanism is operative in various tumor types, including hepatocellular carcinoma, colorectal cancer, and lung adenocarcinoma, suggesting its potential therapeutic relevance. Therapeutic strategies targeting disulfidptosis include modulation of metabolic pathways—such as the use of GLUT1 or G6PD inhibitors—to selectively induce this form of cell death in cancer cells. This review systematically summarizes current understanding, aiming to elucidate the unique mechanisms and therapeutic potential of disulfidptosis, and provides a foundational framework for future studies and the development of innovative strategies targeting tumor metabolic vulnerabilities.