Fraxetin targets PTGR2 to produce anti-inflammatory effects on the host and reduce the toxicity of Pseudomonas aeruginosa

Although the natural product fraxetin exhibits diverse biological functions, particularly in anti-inflammatory activities, its specific mechanism of action has remained unclear. Employing affinity-based protein profiling (AfBPP), prostaglandin reductase 2 (PTGR2), a key enzyme responsible for terminal inactivation of prostaglandins, is identified as the cellular target of fraxetin in host cells. Additionally, fraxetin is discovered to significantly reduce the production of pyoverdine in Pseudomonas aeruginosa, an essential virulence factor in its acute infections thereby protecting hosts from P. aeruginosa infection through anti-virulence mechanisms. Overall, our study elucidates the precise target of fraxetin and highlights the multifaceted nature of this bioactive natural product from both host and pathogen perspectives.