Disulfidptosis: A novel cell death mechanism with pathological significance and therapeutic potential in diseases.

Abstract

Programmed cell death participates in diverse physiological and pathological processes. The identification of disulfidptosis reveals that disulfide stress-induced cytoskeletal disintegration constitutes a targetable biological process mediated through pathways such as SLC7A11-dependent cystine metabolism, offering potential therapeutic avenues for disease intervention. Disulfidptosis involves activation of specific molecular pathways, including SLC7A11-mediated cystine uptake, NADPH depletion, aberrant intracellular disulfide accumulation, filamentous actin collapse, and dysregulation of the antioxidant system, ultimately leading to cell death and contributing to disease progression. Furthermore, comparison between disulfidptosis and other established cell death modalities, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, further underscores its unique biological characteristics and research significance, enabling intervention in disease progression. By targeting these pathways, we systematically integrated pharmacological agonists and inhibitors of key targets, such as SLC7A11-dependent cystine metabolism, to promote or inhibit disulfidptosis, thereby restoring cellular homeostasis disrupted by diseases including cancer, neurodegeneration, ischemia/reperfusion injury, autoimmune diseases, metabolic syndrome, and sepsis. This highlights the potential of disulfidptosis as a therapeutic target. We identified that therapeutic strategies targeting disulfidptosis converge on the core pathogenic axis of "redox imbalance, disulfide stress, actin cytoskeleton collapse." These strategies exhibit disease-dependent bidirectionality-inducing disulfidptosis to selectively eliminate cancer cells in neoplastic diseases while suppressing this process to protect functional cells in non-neoplastic conditions. This review explores the current understanding of the molecular mechanisms and key regulatory nodes of disulfidptosis, deepening our comprehension of the role of disulfidptosis in human health and disease while revealing actionable targets and future research directions. SIGNIFICANCE STATEMENT: The discovery of disulfidptosis enriches understanding of programmed cell death, providing a foundation for targeting SLC7A11-mediated cystine metabolism and other key pathways to treat various diseases and offering new approaches for managing pathological processes previously considered intractable. As molecular mechanistic understanding advances, these emerging therapeutic strategies may open new research avenues, although clinical translation and efficacy require further validation.