The ACOD1-itaconate axis in anti-neuroinflammation and protection against neurodegenerative diseases

Chronic neuroinflammation mediated by activated microglia constitutes a central pathogenic mechanism underlying neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Despite substantial progress in elucidating disease mechanisms, effective disease-modifying therapies remain elusive. Recent investigations have identified the aconitate decarboxylase 1 (ACOD1)-itaconate axis, a mitochondrial enzyme-metabolite pathway, as a critical immunometabolic checkpoint that regulates inflammation across diverse pathological contexts. This pathway exerts immunomodulatory effects through multiple mechanisms, including succinate dehydrogenase inhibition, nuclear factor erythroid 2-related factor 2 activation via Kelch-like ECH-associated protein 1 alkylation, and suppression of the NOD-like receptor protein 3 inflammasome. Emerging evidence has demonstrated that ACOD1-derived itaconate and its cell-permeable derivatives modulate neuroinflammation, preserve synaptic integrity, and ameliorate cognitive deficits in preclinical models of neurodegenerative diseases. This review critically synthesizes current evidence on the ACOD1-itaconate axis in central nervous system pathology, with particular emphasis on its roles in AD, PD, MS, and metabolic cognitive dysfunction. We further summarize the mechanistic insights and therapeutic potential of targeting this pathway in neuroinflammation-driven cognitive impairment. Additionally, this review uniquely integrates infection-induced and diet-induced cognitive impairment models and provides a critical perspective on translating this pathway from the bench to the bedside.