{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:06:53Z","timestamp":1790057213865,"version":"4.0.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"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>Objective<\/jats:title>\n                    <jats:p>SLC1A6 remains poorly characterized in bladder cancer. This study investigated its expression pattern, clinical relevance, cellular localization, functional implications, and potential pharmacological modulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bulk transcriptomic cohorts, clinical data, single-cell RNA-seq data, and spatial transcriptomic data were analyzed to characterize SLC1A6 in bladder cancer. We evaluated SLC1A6 expression, prognosis, clinicopathological associations, immune microenvironment features, metabolic programs, and predicted drug sensitivity. Single-cell and spatial analyses were used to identify the main cellular source and tissue localization of SLC1A6. Virtual knockout analysis was used to estimate pathway changes after SLC1A6 depletion. SLC1A6 expression was validated using Human Protein Atlas immunohistochemistry images, paired clinical tissue Western blotting, and qPCR\/Western blotting in bladder cancer cell lines. Structure-based virtual screening and molecular docking were performed, followed by functional testing of ethyl rosmarinate in T24 and UM-UC-3 bladder cancer cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SLC1A6 was upregulated in bladder cancer tissues and cell lines and was associated with poor survival, advanced clinicopathological features, immunosuppressive characteristics, metabolic remodeling, and poorer survival outcomes in immunotherapy-treated cohorts. Single-cell and spatial analyses showed that SLC1A6 was mainly enriched in epithelial tumor cells and epithelial-dominant tumor regions. SLC1A6-high epithelial cells showed enhanced lipid- and glycan-related metabolic activity. Virtual knockout analysis predicted broad pathway alterations after SLC1A6 depletion. Virtual screening prioritized ethyl rosmarinate as a candidate SLC1A6-interacting compound, and CETSA further supported its cellular target engagement with SLC1A6. In T24 cells, ethyl rosmarinate reduced SLC1A6 protein expression and suppressed migration, colony formation, and invasion. Consistent phenotypic effects on migration, clonogenic growth, and invasion were further observed in UM-UC-3 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>SLC1A6 is an epithelial-enriched, clinically relevant molecule associated with malignant progression, immune suppression, and metabolic remodeling in bladder cancer. Ethyl rosmarinate may represent a candidate compound for further investigation in SLC1A6-related bladder cancer models.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1895264","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:41:12Z","timestamp":1790055672000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure-based virtual screening identifies ethyl rosmarinate as a SLC1A6-targeted therapeutic candidate for bladder cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Hao","family":"Wang","sequence":"first","affiliation":[{"name":"School of Clinical Medicine, Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongquan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/s41586-023-06234-x","article-title":"Y chromosome loss in cancer drives growth by evasion of adaptive immunity","volume":"619","author":"Abdel-Hafiz","year":"2023","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1186\/s13059-025-03784-3","article-title":"xCell 2.0: robust algorithm for cell type proportion estimation predicts response to immune checkpoint blockade","volume":"26","author":"Angel","year":"2025","journal-title":"Genome Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2882","DOI":"10.21037\/tcr-20-1751","article-title":"Systemic characterization of the SLC family genes reveals SLC26A6 as a novel oncogene in hepatocellular carcinoma","volume":"10","author":"Cao","year":"2021","journal-title":"Transl. 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