{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:25:20Z","timestamp":1787034320996,"version":"build-2736575974"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Castration-resistant prostate cancer (CRPC) develops through tumor-cell plasticity, androgen receptor (AR) pathway rewiring, and immune\/stromal changes under therapeutic pressure. Because metastatic CRPC often responds incompletely to immunotherapy and AR-directed treatment, cell-resolved analyses may help place putative drug-response factors within their tissue context. We examined whether secretory leukocyte protease inhibitor (SLPI), an epithelial secreted factor with immunoregulatory functions, is related to epithelial-state changes and enzalutamide response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Public single-cell RNA-sequencing data from localized prostate cancer and metastatic CRPC (GSE274229) were analyzed using Seurat-based preprocessing, cell-type annotation, UCell pathway\/state scoring, CellChat ligand-receptor inference, CopyKAT malignant-cell inference, Monocle2 trajectory analysis, hdWGCNA network analysis, and TCGA-PRAD clinical association analysis. SLPI was evaluated in 22Rv1 and C4-2 prostate cancer models using stable overexpression, qRT-PCR, proliferation, colony formation, migration, AR-pathway modulation, enzalutamide dose-response, and Annexin V\/PI apoptosis assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Progression to mCRPC was accompanied by altered epithelial-immune\/stromal communication and shifts in inflammatory, extracellular-matrix, growth-factor, and immune-regulatory signaling. Putative malignant epithelial populations showed reduced AR-dependency and luminal-identity scores together with increased stress-adaptation and plasticity programs. Network and clinical association analyses highlighted SLPI as a progression-related epithelial factor with outcome relevance.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , SLPI expression was lower in prostate cancer cells than in RWPE-1 cells, and SLPI overexpression suppressed proliferation, migration, and clonogenic growth. AR-pathway modulation showed reciprocal changes in SLPI expression: androgen deprivation and AR knockdown increased SLPI expression, whereas DHT-mediated AR reactivation reduced SLPI expression. SLPI overexpression enhanced enzalutamide-induced growth inhibition and apoptosis in the tested cell-line models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings place SLPI at the intersection of AR-pathway state, epithelial adaptation, immune-context changes, and enzalutamide sensitivity in CRPC. SLPI may represent a therapy-response-associated epithelial factor in prostate cancer, but further protein-level, loss-of-function,\n                      <jats:italic>in vivo<\/jats:italic>\n                      , and clinically annotated validation will be required.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1876355","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:37:09Z","timestamp":1787031429000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["SLPI is associated with AR-regulated epithelial adaptation and enzalutamide sensitivity in castration-resistant prostate cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhen","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Urology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyong","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingjun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2492","DOI":"10.1200\/JCO.2017.77.6880","article-title":"Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study","volume":"36","author":"Aggarwal","year":"2018","journal-title":"J. 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