The emerging roles of disulfidptosis in cancer

Cancer persists as a significant global health burden, with conventional therapeutic approaches frequently constrained by drug resistance and disease relapse, underscoring the urgent requirement for innovative treatment modalities. Recent advances in regulated cell death have uncovered promising therapeutic avenues for cancer. Amidst these newly identified processes, disulfidptosis-a distinct type of programmed cell death triggered by disulfide stress-has garnered significant attention because of its specific metabolic reliance. The underlying mechanism centers on pathological intracellular cystine accumulation coupled with depletion of NADPH reducing equivalents, stemming from elevated levels of the cystine transporter SLC7A11 during metabolic stress states such as glucose deprivation. This cascade induces aberrant disulfide bonding followed by actin cytoskeleton disruption, ultimately resulting in cellular demise. Evidence suggests that disulfidptosis-related genes exhibit altered expression across various malignancies, including lung, liver, and colorectal cancers, and are strongly correlated with disease progression and patient outcomes. Prognostic models constructed based on bioinformatics not only demonstrate good predictive efficacy but also reflect characteristics of the tumor immune microenvironment. This process reveals a fundamental weakness in cancer cells after metabolic reprogramming, establishing the induction of disulfidptosis via SLC7A11 inhibition or modulation of associated metabolic pathways as a promising new anticancer approach. It also provides a rationale for combination strategies with chemotherapy, targeted therapy, and immunotherapy. Nonetheless, its interaction with different cell death mechanisms (including ferroptosis), the variability observed across various cancer types, and the translation to clinical applications remain significant challenges and key avenues for future investigation.