Ferroptosis in Alzheimer’s disease: molecular mechanisms and advances in therapeutic strategies
Ze Zhou, Yiting Zhang, T. Liu, Haixia Tang, Lun Yang, Lun Yang, Lu Yin, Jiaobao Liao, Shuowei Zhang, Zukun Chen, Ling Yang, Ling Yang
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by the continuous decline of cognitive functions. Its pathogenesis involves complex, multidimensional interactions among various molecular pathways. In recent years, ferroptosis, a regulated form of iron-dependent cell death, has emerged as a crucial contributor to AD progression. Ferroptosis is defined by the accumulation of lipid peroxides and inactivation of glutathione peroxidase 4 (GPX4), and is typically initiated in the context of disrupted iron homeostasis, aberrant lipid metabolism, and mitochondrial dysfunction in the brain. This review comprehensively delineates the molecular mechanisms underlying dysregulated iron metabolism in AD and proposes an integrative "iron-lipid-energy-inflammation" axis as a pathological framework. Particular attention is given to the GPX4 signaling pathway as a central hub linking lipid peroxidation, mitochondrial damage, and immune responses. Moreover, ferroptosis can propagate through intercellular mechanisms involving the release of damage-associated molecular patterns (DAMPs), dysregulation of immune checkpoints, and exosome-mediated signaling, collectively driving microglial activation, T-cell infiltration, and blood-brain barrier disruption, culminating in systemic immune imbalance. We further evaluate multiple therapeutic strategies targeting ferroptosis, including iron chelators, antioxidants, GPX4 activators, and lipoxygenase inhibitors. Based on emerging evidence, we propose a precision medicine approach that incorporates ferroptosis subtyping, multi-omics analysis, and targeted delivery systems. Ferroptosis represents a promising frontier for early diagnosis and intervention in AD, potentially enabling the development of causality-oriented, mechanism-based therapies.