{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:59:43Z","timestamp":1780898383753,"version":"3.54.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Arecoline, the major alkaloid of areca nut, is a common exposure in chewing products, but its relationship with prostate cancer (PCa) is unclear. We integrated network toxicology, bulk RNA machine learning, single-cell transcriptomics, molecular simulation, and\n                    <jats:italic>in vitro<\/jats:italic>\n                    validation to prioritize candidate molecular nodes potentially linking arecoline exposure to PCa-related alterations. Potential arecoline targets were intersected with PCa-related genes, followed by protein\u2013protein interaction and enrichment analyses. Candidate genes were prioritized using TCGA-PRAD and external GEO cohorts, then refined in GWAS-relevant epithelial subpopulations from GSE141445. AR was further evaluated by the Human Protein Atlas, molecular docking, molecular dynamics, RT-qPCR, and Western blotting. We identified 97 overlapping targets enriched mainly in apoptosis-, p53-, and MAPK-related pathways. The optimal bulk RNA model showed good external performance (AUC = 0.956). Integrative analyses identified androgen receptor (AR) as the only consensus core gene. AR-high epithelial cells showed increased androgen response, mTORC1 signaling, and MYC targets. Molecular simulation provided computational support for structural compatibility between arecoline and AR, while\n                    <jats:italic>in vitro<\/jats:italic>\n                    experiments showed increased AR mRNA and protein expression after arecoline treatment in LNCaP cells. These findings suggest AR as a plausible candidate molecular node linking arecoline exposure to PCa-related molecular alterations and provide a hypothesis-generating framework for future mechanistic and exposure-focused studies.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1851696","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:33:32Z","timestamp":1780896812000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the molecular link between arecoline exposure and prostate cancer-related alterations: integrative evidence from network toxicology, single-cell transcriptomics, molecular simulation, and experimental validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Xinyao","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Urology, Santai Hospital Affiliated to North Sichuan Medical College","place":["Mianyang, Sichuan, China"]},{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, Santai Hospital Affiliated to North Sichuan Medical College","place":["Mianyang, Sichuan, China"]},{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Urology, Santai Hospital Affiliated to North Sichuan Medical College","place":["Mianyang, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lunhong","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Urology, Santai Hospital Affiliated to North Sichuan Medical College","place":["Mianyang, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, Santai Hospital Affiliated to North Sichuan Medical College","place":["Mianyang, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, Santai Hospital Affiliated to North Sichuan Medical College","place":["Mianyang, Sichuan, China"]},{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1007\/s10552-012-0113-9","article-title":"Areca nut chewing and esophageal squamous-cell carcinoma risk in Asians: a meta-analysis of case-control studies","volume":"24","author":"Akhtar","year":"2013","journal-title":"Cancer Causes Control"},{"key":"B2","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1177\/1757913918785398","article-title":"Areca nut trade, globalisation and its health impact: perspectives from India and south-East Asia","volume":"139","author":"Arora","year":"2019","journal-title":"Perspect. 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