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Life sciences · Journal article
Frontiers in Aging Neuroscience · November 3, 2026
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The mechanisms driving irreversible neural cell loss in neurodegenerative diseases remain elusive. The collapse of cellular redox balance has unveiled a complex network of emerging metabolic cell death modalities that extend far beyond classical apoptosis. Disulfidptosis, a newly identified form of regulated cell death driven by disulfide stress and uniquely marked by actin cytoskeletal collapse, adds a critical dimension to this network. This review establishes an integrative framework—from sulfur metabolic imbalance to cytoskeletal collapse—for understanding this lethal pathway specifically within the nervous system. we focus on three features that are distinctive to neural tissue: the neuron–glia metabolic coupling that dictates which cell type is most vulnerable; the contrast between chronic disulfide stress dynamics in neurodegeneration and acute stress dynamics in ischemic stroke; and the blood–brain barrier (BBB) and cellular heterogeneity constraints that shape translational strategies. We first establish the cystine/cysteine cycle as the central hub of sulfur metabolism, revealing how it transforms from an antioxidant defense into a lethal driver of disulfide stress upon crossing a critical threshold. We then systematically dissect the molecular machinery of disulfidptosis, centered on NADPH depletion, the SLC7A11 bidirectional paradox, and aberrant cytoskeletal crosslinking. By systematically comparing disulfidptosis with ferroptosis and cuproptosis, we identify the SLC7A11-cystine-NADPH axis as a shared regulatory node. We further discuss how this mechanism may converge to contribute to neural cell injury across chronic neurodegenerative and acute neurological conditions, including Alzheimer’s disease and Parkinson’s disease, and may also extend to acute neurological conditions such as ischemic stroke. Finally, we propose a dual neuroprotective strategy targeting disulfidptosis and highlight its biomarker potential. Collectively, this review offers a new paradigm for understanding metabolic cell death in neurodegenerative diseases and lays a theoretical foundation for neuroprotective strategies targeting disulfide homeostasis.