The SLC7A11 Thermostat: A Molecular Signaling Switch Between Ferroptosis and Disulfidptosis in Neurodegenerative Disease

Neurodegenerative diseases are characterized by a metabolic paradox, a balance regulated at the molecular level by a narrow set of redox-sensitive signaling checkpoints. The cystine/glutamate antiporter SLC7A11 plays a central role in this challenge. Traditionally recognized as an antioxidant guardian that prevents ferroptosis through NRF2-KEAP1-driven glutathione synthesis, SLC7A11 can become a burden under metabolic stress. Under glucose restriction or mitochondrial dysfunction, impaired NADPH regeneration prevents cells from reducing imported cystine, leading to disulfide stress in cytoskeletal actin-binding proteins and a novel form of regulated cell death called disulfidptosis. We suggest that neural cell fate and intercellular redox support depend not only on the presence of SLC7A11 activity but also on its specific calibration in each cell type, taking into account cystine availability, glutamate management, and NADPH regeneration. Since baseline system Xc⁻ activity in the CNS is primarily observed in astrocytes and microglia, this regulatory mechanism may operate both within individual cells and across cell types via the astrocyte–neuron metabolic network. Within this proposed framework, insufficient SLC7A11 activity may increase ferroptotic susceptibility, whereas sustained cystine uptake under severe NADPH limitation may create conditions permissive for disulfidptosis. In Alzheimer’s disease, chronic cerebral glucose hypometabolism might lead to disulfide stress in neural cells with high SLC7A11 levels, although the typical disulfidptosis process has not yet been confirmed in vivo. We argue that traditional antioxidant supplements or SLC7A11 modulation are unlikely to succeed without understanding this dual-risk profile at the level of molecular pathways. We propose shifting toward precise adjustment via biomarker-guided redox modulators and metabolic priming to enhance NADPH reserves. By examining SLC7A11 as a dynamic molecular regulator, this review offers a hypothesis-generating framework that may help resolve conflicting findings and inform the development of focused neuroprotective approaches relevant to the molecular neurobiology of neurodegenerative disease.