ABSTRACT Despite numerous therapeutic strategies targeting specific programmed cell death pathways, effectively eliminating malignant colorectal cancer (CRC) remains a significant challenge. Disulfidptosis, a newly identified form of cell death, is characterized by rapid NADPH depletion and abnormal disulfide bond formation in cytoskeletal proteins in cells with high SLC7A11 expression under glucose starvation. Given the aberrant expression of SLC7A11 and the hypermetabolic phenotype of CRC cells, targeting the disulfidptosis pathway offers a promising therapeutic approach for CRC treatment. Here, we developed a binuclear ruthenium complex, RuSSRu, bridged by a disulfide bond, to effectively induce the disulfidptosis pathway in CRC cells. Under two‐photon excitation, RuSSRu generates reactive oxygen species (ROS), leading to lysosomal damage and initiating cellular escape mechanisms. Crucially, this process triggers a cascade of metabolic disruptions, including an accumulation of disulfide bonds and ROS‐induced NADPH depletion, ultimately resulting in cytoskeletal collapse and disulfidptosis. The synergistic interaction between disulfidptosis and lysosomal damage‐induced apoptosis amplified tumor cell death, unveiling a novel mechanism and a versatile therapeutic strategy platform for CRC management.
He et al. (Mon,) studied this question.