Glucose Deprivation-Induced Disulfidptosis via the SLC7A11-INF2 Axis: Pan-Cancer Prognostic Exploration and Therapeutic Validation.

Abstract

Disulfidptosis, a novel form of regulated cell death, involves cytoskeletal collapse due to excessive disulfide bond formation, linking metabolism and reactive oxygen species to potential cancer therapy targets. Recent multi-omics studies highlight the prognostic value of disulfidptosis-related gene (DRG) signatures in pan-cancers; however, the molecular mechanisms underlying their biological functions and therapeutic relevance remain poorly defined. Herein, a DRG score model is constructed using LASSO Cox regression across 33 cancer types, and a nomogram incorporating the DRG score is developed for prognostic prediction. The tumor microenvironment, mutation profiles, and immunotherapy responses are analyzed. The DRG score serves as an independent prognostic factor across cancers, correlating with poor outcomes and malignant features. Glucose deprivation induces disulfidptosis in SLC7A11^high cells (high SLC7A11 expression), especially in cancers with a high DRG score, such as ovarian cancer. Silencing INF2 prevents disulfidptosis and decreases susceptibility to irofulven, which can be reversed by GLUT inhibitors. SLC7A11 knockdown reduces disulfidptosis, restores ATP/NADPH levels, and protects the cytoskeleton under glucose deprivation, whereas INF2 knockdown impairs cell migration. Moreover, the DRG scores predict prognosis and therapeutic responses. The SLC7A11-INF2 axis regulates disulfidptosis, migration, and drug sensitivity, highlighting its potential as a marker of metabolic vulnerability in ovarian cancer.