Cyclo(Ser-Tyr) L/D spatial isomerism exerts opposing effects on benign prostatic hyperplasia.

OBJECTIVE

To investigate the role of two isomers Cyclo (L-Ser-L-Tyr) and Cyclo (D-Ser-L-Tyr) in benign prostatic hyperplasia. Additionally, it seeks to elucidate their mechanisms of action through both in vitro and in vivo experiments.

METHODS

Benign prostatic hyperplasia (BPH) was induced using testosterone propionate. The pharmacological effects of Cyclo (L-Ser-L-Tyr) and Cyclo (D-Ser-L-Tyr) were evaluated. Efficacy and safety were assessed by measuring prostate weight, calculating the prostate index, and conducting histopathological and biochemical analyses. Mechanistic studies incorporated transcriptomics, immunohistochemistry, CCK-8 assays, siRNAs transfection, Western blotting, molecular docking, and molecular dynamics simulations.

RESULTS

Cyclo (L-Ser-L-Tyr) reduced prostate index, attenuated prostatic epithelial hyperplasia and interstitial fibrosis, lowered TNF-α and IL-1β levels, and suppressed inflammation. In contrast, finasteride fails to alleviate prostate fibrosis, while Cyclo (D-Ser-L-Tyr) showed no therapeutic effect and significantly increased serum ALT and AST, indicating potential hepatotoxicity. Transcriptomic analysis showed that Cyclo (L-Ser-L-Tyr) reversed elevated expression of BPH-associated genes and affected pathways including cancer, apoptosis, p53, and MAPK signaling. In prostate tissues and cells, Cyclo (L-Ser-L-Tyr) reduced protein levels of AR and BCL-2. In BPH-1 cells, AR knockout markedly decreased BCL-2 expression. Molecular dynamics simulations showed that Cyclo (L-Ser-L-Tyr) forms a stable complex with AR.

CONCLUSION

Cyclo (L-Ser-L-Tyr) ameliorates BPH by modulating the AR/BCL-2 axis and inflammatory mediators, whereas Cyclo (D-Ser-L-Tyr) is ineffective and may be hepatotoxic. These results support the clinical potential of Cyclo (L-Ser-L-Tyr).