Oxidative stress in neurodegeneration: from a simple insult to a dynamic regulator

OBJECTIVES: To evaluate the central role of oxidative stress in neurodegenerative diseases, and to explore its dynamic regulatory features, underlying signaling pathways, and molecular mechanisms, as well as advanced technological strategies for antioxidant intervention. METHODS: This review comprehensively evaluated existing literature on oxidative stress in neurodegenerative diseases. It analyzed key regulatory pathways (Nrf2, Keap1, AMPK, mTOR) and molecular processes, including ferroptosis, NETosis, and mitochondrial quality control systems, along with oxidative damage to DNA, lipids, and proteins. The review also assessed advanced technological approaches such as subcellular organelle targeting, nanocarrier delivery systems (e.g. gold nanoparticles, liposomes for glutathione delivery), and single-cell/spatial omics technologies (e.g. single-cell redoxomics, spatial transcriptomics). RESULTS: Oxidative stress exhibits dynamic features, generating protective signals in early stages but transitioning into destructive factors later. A major obstacle for current antioxidant therapies is the blood-brain barrier. Breakthrough strategies identified include precision targeting at the subcellular level, functionalized nanoparticles for efficient antioxidant delivery, and the integration of single-cell redoxomics with spatial transcriptomics to identify specific biomarkers and enable personalized treatments. DISCUSSION: By integrating novel molecular mechanisms and advanced technological resources, this review redefines oxidative stress not as a singular event but as a complex, dynamically regulated system in neurodegenerative diseases. This reconceptualization provides new perspectives for developing targeted and personalized therapeutic interventions.