Icariin against neuroinflammation: emerging evidence for gut-brain axis modulation involving short-chain fatty acids, vagal signaling, and extracellular vesicles

Neuroinflammation is a central pathological process in a wide range of central nervous system disorders, yet therapeutic strategies directed solely at single inflammatory targets have shown limited efficacy. Gut–brain axis dysfunction may contribute to neuroinflammatory progression through interconnected metabolic, immune, neural, and vesicle-associated routes. Icariin, a major flavonoid glycoside from Epimedii Folium, has attracted attention because of its anti-inflammatory, neuroprotective, and microbiota-modulating properties. In this review, we summarize current evidence for the anti-neuroinflammatory effects of icariin and explicitly stratify the evidence into three levels: direct icariin-related findings, icariin-related findings without causal gut–brain validation, and mechanisms inferred from broader gut–brain axis biology. Available studies provide relatively stronger support for intestinal barrier protection, microbiota remodeling, peripheral cytokine suppression, and central inflammatory pathway regulation. In contrast, short-chain fatty acid (SCFA)-associated signaling, vagal neuroimmune communication, and extracellular vesicle (EV)-mediated cargo transfer remain plausible but incompletely validated candidate routes. We further compare icariin with its major microbial metabolites, especially icariside II and icaritin, because oral icariin may act partly through metabolite-mediated exposure rather than through robust brain penetration of the parent compound. Major limitations include insufficient causal perturbation, incomplete organ-specific pharmacokinetic data, inter-individual microbiota variability, and uncertain therapeutic time windows. Overall, icariin emerges as a promising multi-target natural product for anti-neuroinflammatory research, but the causal hierarchy and translational relevance of proposed gut–brain pathways require direct validation.