Luteolin in Safflower Leaves Suppresses Microglial Inflammation Through FOXO3-Mediated Trem2 Transcription

Neuroinflammation driven by microglial activation is a hallmark of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial inflammation, yet strategies to modulate its expression remain limited. Safflower leaves, a vegetable rich in flavonoids-particularly luteolin-were previously shown to attenuate neuroinflammation, reduce oxidative stress, and ameliorate cognitive impairment in APP/PS1 mice. Here, we demonstrated that safflower leaves inhibit microglial inflammation and upregulate TREM2 in APP/PS1 mice. Luteolin, the major active flavonoid in safflower leaves, exerted anti-inflammatory effects in lipopolysaccharides (LPS)-activated microglia. Mechanistically, luteolin enhanced <i>Trem2</i> transcription by activating forkhead box protein O3 (FOXO3), a novel transcriptional regulator of <i>Trem2</i> identified through promoter analysis. FOXO3 binding to the <i>Trem2</i> promoter was essential for this regulation, and luteolin further promoted FOXO3 nuclear translocation. Crucially, <i>Trem2</i> knockdown attenuated luteolin's anti-inflammatory effects, confirming TREM2 as a key mediator. Overall, our study reveals the FOXO3-TREM2 axis as a potential therapeutic target for neuroinflammation and highlights luteolin present in safflower leaves as a candidate dietary intervention for AD, providing new mechanistic insights into the anti-inflammatory activity of this natural antioxidant.