Metabolic cell death networks in Alzheimer’s disease: mechanistic links and therapeutic perspectives of ferroptosis, cuproptosis, and disulfidptosis

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized primarily by progressive cognitive impairment, whose pathogenesis involves multiple pathological processes including protein deposition, metal homeostasis dysregulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. In recent years, metabolism-related cell death modalities such as ferroptosis, cuproptosis, and disulfidptosis have gradually been recognized as potentially involved in neuronal damage in Alzheimer’s disease. This review summarizes the fundamental mechanisms of ferroptosis, cuproptosis, and disulfidptosis, along with their research evidence in AD. Ferroptosis is primarily driven by iron imbalance, lipid peroxidation buildup, and impaired GPX4 defense. This process exhibits a bidirectional amplification loop with Aβ and tau pathologies. Cuproptosis contributes to neuronal damage through abnormal copper accumulation, FDX1-related mitochondrial protein lipoylation dysfunction, loss of iron-sulfur cluster proteins, and proteotoxic stress. Disulfidptosis links glucose metabolism disorders, insufficient reducing power, and actin cytoskeleton vulnerability, providing novel insights into metabolic stress and structural damage in AD. Furthermore, the three modes of cell death can undergo cross-regulation through the SLC7A11–NADPH–GSH/GPX4 axis, the FDX1–DLAT/DLST–iron-sulfur cluster axis, as well as upstream factors such as p53, NRF2, and AMPK. Metabolic cell death may constitute a critical pathological network in AD. Targeting these death pathways and their shared hubs is expected to provide new directions for disease stratification, biomarker development, and disease-modifying therapies.