Fisetin Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Targeting Myeloid Differentiation Factor 88.

Acute lung injury (ALI), a severe respiratory syndrome driven by dysregulated inflammatory cascades, urgently requires novel therapeutic strategies. The activation of the MyD88 (Myeloid differentiation factor 88)-mediated TLR (Toll-like receptor) inflammatory signaling pathway plays a crucial role in the pathophysiology of ALI, while minimally involving interferon-mediated responses. Targeting MyD88 offers a promising approach for ALI drug development. Here, we employed surface plasmon resonance (SPR) and in vitro anti-inflammatory screening methods to evaluate the interaction of candidate drugs with MyD88 and their anti-inflammatory activity. This was followed by anti-inflammatory verification in lipopolysaccharide (LPS)-induced ALI mice. Our findings reveal that Fisetin, a flavonoid derived from Cotinus coggygria, exhibited the strongest MyD88-binding affinity and suppressed MyD88 homodimerization, thereby blocking downstream NF-κB and MAPK activation. In LPS-challenged mice, Fisetin significantly reduced pulmonary inflammatory levels, decreased lung wet/dry ratio, and attenuated neutrophil infiltration. In conclusion, Fisetin emerges as a novel MyD88 inhibitor that disrupts TLR-driven inflammatory amplification, positioning it as a phytotherapeutic candidate for ALI.