Bioactive Natural Products Targeting Androgen Receptor Signaling in Prostate Cancer: A Systematic Review

Background: Prostate cancer remains a leading cause of male cancer-related mortality, largely driven by the dysregulated activation of the androgen receptor (AR) signaling pathway. The emergence of resistance, particularly in castration-resistant prostate cancer (CRPC), necessitates the discovery of innovative therapeutic approaches. This systematic review aims to consolidate contemporary evidence regarding natural products as bioactive alternatives capable of targeting the AR signaling axis. Methods: Adhering to PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, and ScienceDirect databases. The review identified and qualitatively analyzed 15 original research studies that investigated the efficacy and mechanisms of various natural compounds in modulating AR signaling. Results: The analysis reveals that natural products deactivate the AR signaling axis through diverse mechanisms. Neoisoliquiritin and α-terthienyl were found to suppress AR expression, activity, and nuclear translocation. Notably, α-mangostin facilitates the degradation of the AR-V7 splice variant, a key driver of treatment resistance. Manzamine A inhibits AR biosynthesis by targeting the transcription factor E2F8. Furthermore, alternative pathways are modulated through 5-α-reductase inhibition (Annona muricata compounds) and the activation of the non-classical membrane receptor ZIP9 by (-)-epicatechin to induce apoptosis. Conclusions: The emergence of resistance, particularly in castration-resistant prostate cancer (CRPC), necessitates the exploration of innovative therapeutic approaches. This systematic review consolidates contemporary evidence regarding natural products as potential bioactive alternatives for modulating the androgen receptor (AR) signaling axis. Rather than providing a definitive clinical roadmap, this work establishes a preclinical framework for identifying substances that may deactivate the receptor, break down its resistant forms, or prevent nuclear translocation.