| Summary: | The pursuit of anti-inflammatory agents has led to intensive research on the inhibition of soluble epoxide hydrolase (sEH) and cytokine production using medicinal plants. In this study, we evaluated the efficacy of <i>cis</i>-khellactone, a compound isolated for the first time from the roots of <i>Peucedanum japonicum</i>. The compound was found to be a competitive inhibitor of sEH, exhibiting an IC<sub>50</sub> value of 3.1 ± 2.5 µM and <i>k</i><sub>i</sub> value of 3.5 µM. Molecular docking and dynamics simulations illustrated the binding pose of (−)<i>cis</i>-khellactone within the active site of sEH. The results suggest that binding of the inhibitor to the enzyme is largely dependent on the Trp336–Gln384 loop within the active site. Further, <i>cis</i>-khellactone was found to inhibit pro-inflammatory cytokines, including NO, iNOS, IL-1β, and IL-4. These findings affirm that <i>cis</i>-khellactone could serve as a natural therapeutic candidate for the treatment of inflammation.
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