Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. In recent years, two cellular processes have emerged as pivotal drivers of neurodegeneration in AD: mitophagy, the selective autophagic clearance of damaged mitochondria, and ferroptosis, an iron-dependent form of regulated cell death. This review outlines the molecular mechanisms of mitophagy and ferroptosis, with a focus on their interplay in AD. We propose that impaired mitophagy disrupts intracellular redox and iron homeostasis, thereby increasing neuronal susceptibility to ferroptosis. Conversely, ferroptosis-executing events, such as lethal lipid peroxidation, can further exacerbate mitochondrial dysfunction. This establishes a self-amplifying vicious cycle that accelerates disease progression. Furthermore, we summarize potential therapeutic strategies targeting this interactive network (e.g., Urolithin A, ferroptosis inhibitors) and highlight promising directions for future research. In contrast to previous reviews that have focused on each process in isolation, this work synthesizes evidence for a self-amplifying feedback loop between impaired mitophagy and exacerbated ferroptosis in AD. We posit that targeting this self-amplifying loop between mitophagy and ferroptosis may offer a novel and effective therapeutic paradigm for halting Alzheimer's disease progression.
Liu et al. (Fri,) studied this question.