Targeting Metabolism and Disulfidptosis: A Novel strategy for Cancer Therapy

Abstract
Disulfidptosis represents a recently characterized form of programmed cell death driven by an intracellular imbalance between cystine and the vital reductant Nicotinamide Adenine Dinucleotide Phosphate (NADPH). This metabolic perturbation precipitates an excessive accumulation of disulfide bonds within cytoskeletal proteins, ultimately compromising cellular integrity and inducing death. Specifically, under conditions of glucose starvation, the restricted supply of intracellular NADPH fails to reduce the aberrant influx of cystine, thereby triggering the disulfidptotic cascade. This review provides a comprehensive critical synthesis of the molecular mechanisms underlying disulfidptosis, with a particular focus on the pivotal roles of solute carrier family 7 member 11 (SLC7A11) and the Rac1-WAVE Regulatory Complex (WRC) signaling axis. Beyond delineating the mechanistic framework, we contextualize these findings within the broader landscape of translational cancer therapy. We systematically evaluate emerging therapeutic strategies designed to exploit this metabolic vulnerability, including the targeted inhibition of SLC7A11 and the pharmacological modulation of glucose, cystine, and NADPH metabolism (via nicotinamide adenine dinucleotide kinase and the pentose phosphate pathway). Furthermore, we discuss the complex interplay between disulfidptosis, tumor metabolic reprogramming, and the immunosuppressive tumor microenvironment. By critically analyzing these interconnected pathways, this review aims to provide conceptual insights and highlight novel, combinatorial therapeutic avenues for precision oncology.