Chemical proteomic profiling reveals prostaglandin termination enzyme PTGR2 as a key molecular target of natural coumarin fraxetin†

Natural coumarins represent a diverse group of secondary metabolites with a wide range of biological activities. However, their specific molecular targets have remained largely unexplored. Employing chemical proteomics, a comprehensive analysis of the protein targets of the natural coumarin fraxetin has been conducted. Prostaglandin reductase 2 (PTGR2), a key enzyme involved in the final inactivation of prostaglandins, was identified as a primary target of fraxetin. Inhibition of PTGR2 can lead to the accumulation of 15-keto-PGE2, which subsequently activates the Nrf2 signaling pathway and suppresses NF-κB, resulting in notable anti-inflammatory effects. These findings provide novel insights into the molecular targets of fraxetin and other coumarins, which are crucial for fully exploring their therapeutic potential.