Yufei Yang, Qingkun Wang, Zhaojun Wang, Yajing Wang, Beibei Liu, Youao Zhang, Xinyuan Mao, Haitao Sun
FAs play multifaceted roles in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review systematically summarizes current understanding of FA metabolism and its diverse implications in neurodegenerative diseases pathology. Short-chain FAs, primarily generated by gut microbiota, regulate neuroinflammation, gut-brain communication, and blood-brain barrier integrity via epigenetic modifications and immune modulation. Medium-chain FAs exhibit therapeutic potential by improving energy metabolism and neuromuscular function, particularly in amyotrophic lateral sclerosis models. Long-chain PUFAs, notably DHA and EPA, contribute to neuronal membrane integrity, synaptic plasticity, and antioxidant defense, mitigating oxidative stress and neuroinflammation. Conversely, saturated and certain n-6 FAs may exacerbate neurodegeneration through proinflammatory and oxidative pathways. Emerging evidence highlights FA involvement in key pathological processes such as lipid peroxidation, mitochondrial dysfunction, ferroptosis, and blood-brain barrier disruption. Therapeutically, targeted supplementation, dietary modification, microbiome manipulation, and advanced nanotechnology-based delivery systems are promising strategies. Nevertheless, precise therapeutic efficacy depends critically on disease stage, dosage, genetic background, and individual metabolic context. Integrating personalized medicine with precision nutritional strategies and novel drug-delivery platforms offers promising avenues to translate FA-based interventions into clinical practice, potentially improving patient outcomes in the aging global population.