This systematic review examines the emerging interplay between ferroptosis and disulfidptosis, two distinct forms of regulated cell death (RCD) centered on the SLC7A11 (also known as xCT)-mediated metabolic paradox. Traditionally recognized as a potent anti-ferroptotic factor, SLC7A11 imports cystine for glutathione synthesis to neutralize iron-dependent lipid peroxidation. However, the discovery of disulfidptosis identifies SLC7A11 as a metabolic liability, representing a paradigm shift in our understanding of cellular antioxidant defense. This discovery reveals a transformative vulnerability in SLC7A11-overexpressing cells, shifting the focus from conventional survival mechanisms to the consequences of catastrophic structural collapse. Beyond metabolic exhaustion, this review highlights the role of metal dyshomeostasis as a primary driver, spanning from iron-catalyzed ferroptosis to copper-mediated metabolic interference. This conceptual framework redefines the SLC7A11 axis as a targetable “double-edged sword” in therapy-resistant malignancies. Clinical synthesis of multi-omic gene signatures, such as the disulfidptosis- and ferroptosis-related gene prognostic score (DRGPS) and the ferroptosis- and disulfidptosis-related gene (FDRG) scores, demonstrates their robust value in prognostic stratification and in predicting immunotherapy response across malignancies, including lung adenocarcinoma and hepatocellular carcinoma. Furthermore, we evaluate the capacity of disulfidptosis to prime immunogenic cell death (ICD) and remodel the immunosuppressive tumor microenvironment to bypass chemoresistance. By integrating mechanistic insights with clinical data, this review provides a comprehensive framework for targeting the SLC7A11 axis as a transformative therapeutic vulnerability in precision oncology.
Tolbatov et al. (Fri,) studied this question.