Integrated Transcriptomic and Metabolomic Analyses in Characterizing the Anti‐Prostate Cancer Effects of Hederagenin

Hederagenin is a triterpenoid compound extracted from ivy leaves and other natural plant sources. Despite the prominent roles that hederagenin assumes in the fight against cancers, its mechanisms in anti-prostate cancer (PCa) remain inadequately comprehended. In this present study, we found that hederagenin effectively inhibited the proliferation and migration of PCa cells by inducing apoptosis in a dose-dependent manner. Transcriptome analysis and metabolic alterations were employed to identify potential molecular targets and pathways of Hederagenin on PCa cells. RNA-seq analysis discerned 747 differentially expressed genes (DEGs) that were conspicuously enriched within the pathway. Furthermore, metabolomics analysis has revealed that hederagenin significantly impacts the metabolic pathways, specifically in glycerophospholipids, choline metabolism, cholesterol metabolism and autophagy. Finally, we carried out the integrated analysis of the metabolomic data and transcriptomic data and validated them by qRT-PCR and western blot experiments. The transmission electron microscopy (TEM) analysis revealed an augmented generation of autophagosomes in PC-3 cell under treatment with hederagenin. The results indicated that hederagenin significantly increased the expression levels of LC3-II/I and P62 in both PCa cells following co-treatment with chloroquine (CQ). Additional functional analysis demonstrated that the inhibition of autophagy by CQ significantly augmented hederagenin-induced apoptotic cell death. The findings suggest that hederagenin efficaciously elicited apoptosis and autophagy of PCa via the mTOR pathway. In conclusion, we believe our study would provide a systematic perspective on the therapeutic effect of hederagenin, which could contribute to the clinical application of hederagenin combined with autophagy inhibitors as a novel strategy for treating human PCa.