Lycopene regulates microglial M1/M2 polarization by inhibiting MAPK/NF-κB signaling and alleviates neuroinflammation

Persistent neuroinflammation driven by dysregulated M1/M2 polarization of microglia is recognized as a key pathological mechanism in the onset and progression of multiple central nervous system (CNS) disorders. Lycopene (LYC), an important dietary carotenoid, exhibits anti-inflammatory activity; however, its molecular mechanisms regulating microglial state and function remain incompletely understood. This study systematically evaluated the anti-neuroinflammatory and neuroprotective effects of LYC in lipopolysaccharide (LPS)-stimulated human microglia (HMC3), mouse primary microglia, and transgenic zebrafish neuroinflammation models. Results indicate that LYC suppresses LPS-induced proinflammatory phenotypes in microglia by downregulating M1-associated markers (iNOS, TNF-α, IL-1β, CD86) and upregulating M2-associated markers (TGF-β, IL-10, CD206), thereby promoting their transition to an M2-like anti-inflammatory state. In primary microglia, LYC similarly favored an M2-like phenotype and partially rescued the LPS-associated reduction in phagocytosis by increasing the fraction of phagocytic cells and enhancing per-cell microbead uptake. In coculture systems, LPS-activated HMC3 cells with LYC significantly increased the survival rate and reduced apoptosis in subchamber SH-SY5Y cells, demonstrating a marked neuroprotective effect. Mechanistically, LYC markedly reduced LPS-induced phosphorylation of p38, JNK, ERK1/2, and p65, suggesting inhibition of MAPK/NF-κB signaling activation. In vivo experiments further confirmed that LYC improved motor dysfunction in zebrafish, reduced neutrophil infiltration and brain inflammatory responses, attenuated microglia-associated inflammatory activation, and restored neuronal and synapse-related gene expression. In summary, LYC alleviates neuroinflammation and exerts neuroprotective effects by inhibiting MAPK/NF-κB signaling and rebalancing microglial M1/M2 phenotypes, providing a mechanistic basis for its potential as a therapeutic candidate targeting neuroinflammation.