DHA as a systems regulator of neuroinflammation: A narrative review integrating membrane organization, immunometabolism, and inflammatory resolution.

Abstract

Neuroinflammation is a central feature of brain aging and a major driver of neurodegenerative and neuropsychiatric disorders. Conventional anti-inflammatory strategies have produced inconsistent clinical outcomes, reflecting the biological complexity of chronic neuroinflammation and the limited capacity of single-target interventions to modulate interconnected pathogenic pathways. This narrative review synthesizes evidence from mechanistic studies, clinical trials, and meta-analyses identified through structured searches of PubMed, Scopus, and Web of Science. Docosahexaenoic acid (DHA), the predominant omega-3 fatty acid in the brain, modulates neuroinflammatory processes through coordinated effects on membrane organization, intracellular signaling, mitochondrial function, and inflammatory resolution. DHA remodeling of membrane phospholipids alters lipid raft-dependent signaling, attenuates activation of nuclear factor kappa B (NF-κB) and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, enhances mitochondrial bioenergetics and redox homeostasis, and promotes the generation of specialized pro-resolving mediators. Aging-associated processes, including microglial priming, metabolic dysfunction, impaired lipid transport, blood-brain barrier (BBB) dysfunction, and altered glial responsiveness, further reshape DHA availability and therapeutic responsiveness. These factors contribute to heterogeneous clinical outcomes, as intervention studies often fail to account for baseline omega-3 status, genetic variability, metabolic phenotype, formulation-dependent bioavailability, disease stage, and exposure duration. Emerging lipidomic and biomarker-guided approaches may better characterize biological heterogeneity in DHA intervention studies. We propose a systems-level model in which DHA integrates structural, bioenergetic, and immune-resolution domains governing neuroinflammatory homeostasis, adaptive resilience, and vulnerability to neurodegeneration during aging.