Deciphering anti–benign prostatic hyperplasia potential of liangwanoside II based on metabolite profile characterization combined with targeted network pharmacology

Metapanax delavayi (Franch.) J.Wen & Frodin (Araliaceae), known as "liang wang cha" in China, has been used to treat prostatitis as herbal tea in folk. Recent research suggested that aqueous extract of Metapanax delavayi leaves showed an advantage in anti–benign prostate hyperplasia (BPH) activity, and liangwanoside II was the main component of the active fraction. However, the anti–BPH effect of liangwanosdie II remains to be revealed. This study aims to decipher anti–BPH potential of liangwanoside II. The anti–BPH effect was evaluated by testosterone propionate–induced BPH rats after oral administration of liangwanoside II at the doses of 30, 60 and 120 mg/kg in vivo. Then, the metabolites of liangwanoside II in rats were identified using ultra–performance liquid chromatography coupled with quadrupole tandem time–of–flight mass spectrometry (UPLC–Q–TOF–MS). Finally, the targeted network pharmacology combined with experimental verification were explored for the mechanism elucidation in vivo. Liangwanoside II exhibited an anti–BPH effect through reducing the weight of the prostate, prostate index and serum prostatic acid phosphatase level, and improving the prostate tissue morphology in BPH rats. Further, 16 metabolites of liangwanoside II in vivo were identified by UPLC–Q–TOF–MS analysis, in which the prototype compound and 4 metabolites, such as liangwanoside I and serratagenic acid could be absorbed in the plasma and then penetrate the blood–prostate barrier. Then, followed by the targeted network pharmacology and experimental verification, we found that liangwanoside II and its metabolites could jointly involve in the inhibition of the inflammation reaction and hormone imbalance, thus reducing oxidative stress damage, and restoring the balance between cell proliferation and apoptosis, which contributed to the anti–BPH effect of liangwanoside II. The anti–BPH potential of liangwanoside II was revealed using metabolite profile characterization combined with targeted network pharmacology, providing new insight into the development and utilization of liangwanoside II.