The emerging role of disulfidptosis in Alzheimer's disease

Alzheimer's disease (AD) is a chronic neurodegenerative disorder primarily characterized by Aβ deposition and tau hyperphosphorylation. Clinically, AD manifests as progressive episodic-memory loss that ultimately erodes global cognition and the ability to perform activities of daily living. Despite decades of investigation, the molecular underpinnings of AD remain incompletely understood and no disease-modifying therapies are available. Recently, disulfidptosis, a novel form of programmed cell death (PCD) caused by disulfide stress with high expression of SLC7A11 (solute carrier family 7 member 11) under glucose starvation conditions, has emerged as a potential contributor to neurodegeneration. This review systematically summarizes the discovery, molecular features, and regulatory mechanisms of disulfidptosis, and critically evaluates its relevance to AD pathogenesis. We show that disulfidptosis can directly or indirectly modulate pivotal disease pathways, including Aβ accumulation, tau hyper-phosphorylation, and oxidative stress, through interconnected molecular cascades. Furthermore, we also delved into its potential application prospects in AD treatment, including inhibiting SLC7A11 activity, regulating NADPH (Nicotinamide Adenine Dinucleotide Phosphate) levels, targeting actin cytoskeleton dynamics, and antioxidant therapy. By integrating disulfidptosis into the AD landscape for the first time, this review offers a novel mechanistic perspective and identifies actionable therapeutic targets, thereby laying the groundwork for precision strategies against disulfidptosis-driven neurodegeneration.