The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration

Abstract

Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies.

Keywords: Nrf2 pathway; antioxidant therapies; lipid peroxidation; mitochondrial dysfunction; multi-omics integration; neurodegenerative diseases; oxidative stress; precision redox medicine; protein carbonylation; reactive oxygen species (ROS).

Figure 1

Overview of intracellular reactive oxygen species (ROS) generation and antioxidant detoxification. Superoxide (O₂⁻) is generated via electron leakage in the mitochondrial electron transport chain (ETC) and by NADPH oxidases (NOXs), notably NOX2 in microglia. SOD1 converts O₂⁻ into hydrogen peroxide (H₂O₂), which is further neutralized by catalase (CAT), glutathione peroxidase (GPX), and peroxiredoxins (PRX) in the cytosol and peroxisomes. In the presence of Fe²⁺, H₂O₂ undergoes the Fenton reaction to generate highly reactive hydroxyl radicals (•OH). This figure intends to integrate the major subcellular sources of ROS and highlights the enzymatic antioxidant systems responsible for maintaining redox homeostasis in the brain.

Figure 2

This illustrates the role of PTPN1 and PTPN2 inhibitors in regulating cytokine-induced JAK-STAT signaling pathways. Under normal conditions, cytokine binding to its receptor activates the JAK kinases, which phosphorylate downstream targets and drive the transcription of pro-inflammatory genes. PTPN1 and PTPN2, acting as protein tyrosine phosphatases, negatively regulate this pathway by dephosphorylating key signaling intermediates, effectively dampening the inflammatory response. The inhibition of PTPN1/2 prevents their dephosphorylation activity, thereby sustaining JAK-STAT activation and enhancing the production of inflammatory cytokines. This dysregulated signaling is linked to chronic inflammation and oxidative stress, which contribute to neurodegeneration in diseases like ALS, AD, and PD. However, targeted inhibition of PTPN1/2 offers a novel therapeutic approach to restore redox balance by suppressing cytokine-driven inflammation.

Figure 3

This illustrates the Nrf2-Keap1 pathway activation and Nrf2 nuclear translocation in response to oxidative stress. Under normal conditions, Nrf2 is sequestered in the cytoplasm by its inhibitor, Keap1, which facilitates Nrf2 degradation. However, upon exposure to elevated levels of ROS, oxidative modifications to Keap1 result in the release of Nrf2. Freed from Keap1, Nrf2 translocates to the nucleus, where it forms a complex with small Maf (sMaf) proteins and binds to the antioxidant response element (ARE) within the promoter regions of target genes. This binding initiates the upregulation of antioxidant proteins such as SOD, catalase, GPx, and heme oxygenase-1 (HO-1), which collectively neutralize ROS and restore redox homeostasis.