The Role, Mechanism, and Clinical Application Prospects of Itaconate in Neurodegenerative Diseases

Neurodegenerative diseases (NDD) are devastating disorders characterized by progressive neuronal loss, severely impairing cognitive and motor functions. With the global aging population accelerating, NDD prevalence is surging, projected to become the second leading cause of death by 2040. Current therapies remain palliative, failing to halt disease progression, underscoring an urgent need for novel therapeutic strategies. Recent advances highlight itaconate, a tricarboxylic acid cycle metabolite, as a pivotal immunometabolic regulator with potent anti-inflammatory and antioxidant properties. Emerging evidence reveals that itaconate and its derivatives (e.g., 4-OI and DMI) mitigate neuroinflammation and oxidative stress via modulating the Nrf2 pathway, inhibiting NLRP3 inflammasome activation, and blocking the cGAS-STING signaling cascade. These mechanisms not only protect neurons but also enhance regenerative capacity, offering a dual-action therapeutic approach distinct from existing treatments. Importantly, the development of membrane-permeable derivatives addresses previous pharmacokinetic limitations, positioning itaconate-based therapies as clinically translatable candidates. Despite promising preclinical findings, critical gaps persist in understanding disease-specific mechanisms, optimal dosing, and combinatorial synergies. This review synthesizes current knowledge, emphasizing the transformative potential of targeting immunometabolic pathways in NDD. By bridging mechanistic insights with therapeutic innovation, this work aims to accelerate the translation of itaconate from bench to bedside, addressing a pressing unmet medical need in our aging society.