{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T05:12:06Z","timestamp":1783746726974,"version":"3.55.0"},"reference-count":152,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prostate cancer remains one of the most biologically heterogeneous malignancies in men and continues to present major therapeutic challenges despite advances in androgen receptor-targeted therapy and molecular stratification. Increasing evidence suggests that prostate cancer progression is influenced not only by tumor-intrinsic genetic alterations but also by complex interactions involving androgen receptor signaling, inflammatory pathways, metabolic reprogramming, oxidative stress, epigenetic remodeling, immune dysregulation, and gut microbiome-associated signaling. Within this evolving systems-level framework, natural products have attracted increasing attention because of their ability to modulate multiple interconnected molecular pathways. This review examines the molecular basis of prostate cancer progression with particular emphasis on crosstalk among androgen receptor signaling, microbiome-associated regulation, epigenetic adaptation, inflammatory signaling, and tumor microenvironment remodeling. The emerging role of the gut microbiome in androgen metabolism, microbial metabolite production, immune regulation, and endocrine resistance is critically discussed, together with current evidence describing the biological effects of selected phytochemicals including curcumin, epigallocatechin-3-gallate, resveratrol, sulforaphane, quercetin, and genistein. These compounds may influence prostate cancer-associated pathways through modulation of inflammatory signaling, oxidative stress, metabolic adaptation, chromatin remodeling, and microbiome dynamics. Major translational limitations including poor bioavailability, pharmacokinetic variability, microbiome heterogeneity, inconsistent clinical evidence, and incomplete mechanistic understanding are additionally discussed. Rather than considering natural products as isolated anticancer agents, this review adopts a systems-level perspective in which dietary bioactive compounds may function as modulators of interconnected regulatory networks relevant to prostate cancer biology and therapeutic responsiveness.<\/jats:p>","DOI":"10.3390\/ijms27135956","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T14:51:25Z","timestamp":1783003885000},"page":"5956","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Products in Prostate Cancer: Crosstalk Among the Gut Microbiome, Androgen Receptor Signaling, and Epigenetic Regulation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2068-3075","authenticated-orcid":false,"given":"Mohammad Muzaffar","family":"Mir","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4605-6670","authenticated-orcid":false,"given":"Javed Iqbal","family":"Wani","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashid","family":"Mir","sequence":"additional","affiliation":[{"name":"Prince Fahd Bin Sultan Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8785-8429","authenticated-orcid":false,"given":"Muffarah Hamid","family":"Alharthi","sequence":"additional","affiliation":[{"name":"Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1721-7468","authenticated-orcid":false,"given":"Abdullah","family":"Ayed","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0761-6062","authenticated-orcid":false,"given":"Partha","family":"Nandi","sequence":"additional","affiliation":[{"name":"Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5320-3202","authenticated-orcid":false,"given":"Ayyub Ali","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Medical Education, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayaz Khurram","family":"Mallick","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Medical Education, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6838-8901","authenticated-orcid":false,"given":"Mohannad Mohammad S.","family":"Alamri","sequence":"additional","affiliation":[{"name":"Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5524-3008","authenticated-orcid":false,"given":"Mohammed","family":"O\u2019haj","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0259-1786","authenticated-orcid":false,"given":"Tarig Babikir Algak","family":"Khalid","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6819-4688","authenticated-orcid":false,"given":"Adnan","family":"Jehangir","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Department, College of Medicine, King Faisal University, Al Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hany M. 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