Discovery of wedelolactone from Eclipta Prostrata (L.) Linn. as a natural PDE4 inhibitor with potent anti-psoriasis effects

Psoriasis is a chronic inflammatory disorder for which phosphodiesterase-4 (PDE4) inhibitors have emerged as promising therapeutic agents due to an ability to regulate inflammatory signaling pathways. In this study 1200 methanolic extracts from Chinese medicinal plants were screened and Eclipta prostrata (L.) Linn. ( E. prostrata ) was shown to have potent PDE4 inhibitory activity. Bioassay-guided fractionation further demonstrated that the ethyl acetate (EA) fraction exhibited the highest inhibitory activity, leading to the isolation of wedelolactone (WDL) as the principal bioactive compound (IC 50 = 2.8 μM). Molecular dynamics simulations revealed that WDL forms stable interactions with PDE4D through hydrogen bonding and hydrophobic contacts. E. prostrata -EA and WDL significantly suppressed pro-inflammatory cytokines in keratinocytes in vitro . Topical application of WDL demonstrated superior anti-psoriatic efficacy compared to calcipotriol in vivo , as evidenced by reduced Psoriasis Area and Severity Index scores, normalized epidermal thickness, and improved inflammatory cytokine profiles. WDL exhibited favorable metabolic stability in liver microsomes and demonstrated a good safety profile in subacute toxicity assessments with no systemic toxicity. These findings established WDL as a potent and safe topical PDE4 inhibitor, highlighting the potential of WDL as a novel therapeutic candidate for psoriasis and warranting further clinical development.