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Q23002, S22002, S22049 and Q20013"],"award-info":[{"award-number":["grant nos. Q23002, S22002, S22049 and Q20013"]}]},{"name":"the Innovation Team Project of the Affiliated Hospital of Chengdu University","award":["CDFYCX202207"],"award-info":[{"award-number":["CDFYCX202207"]}]},{"name":"the Chengdu Medical Research Projects","award":["grant nos. 2022051, 2023128, 2022181,2023087 and 2023343"],"award-info":[{"award-number":["grant nos. 2022051, 2023128, 2022181,2023087 and 2023343"]}]},{"name":"Young Talents Program of the Affiliated Hospital of Chengdu University and the Program of the Affiliated Hospital of Chengdu University","award":["grant nos. 2020YZZ08, Y202204 and Y202207"],"award-info":[{"award-number":["grant nos. 2020YZZ08, Y202204 and Y202207"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["grant no. 82300869"],"award-info":[{"award-number":["grant no. 82300869"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the 78th Batch of General Funding Projects of China Postdoctoral Science Foundation","award":["2025M782291"],"award-info":[{"award-number":["2025M782291"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Hereditas"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Bladder cancer remains a major urologic malignancy with substantial recurrence and progression risk, underscoring the need for mechanism-informed therapeutic candidates. Ginkgetin, a biflavonoid derived from\n                      <jats:italic>Ginkgo biloba<\/jats:italic>\n                      leaves, has shown antitumor potential in several cancer settings, yet its key signaling axis and actionable molecular node in bladder cancer have not been systematically defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated ginkgetin across multiple bladder cancer cell lines (5637, T24, HT-1376, J82) and normal urothelial cells (SV-HUC-1) using viability assays and IC\u2085\u2080 estimation. Antitumor phenotypes were assessed by colony formation, wound-healing migration assays, EMT marker profiling, and Annexin V\/PI flow cytometry. Network pharmacology and RNA-seq were integrated to prioritize enriched pathways, followed by western blot validation of PI3K\/AKT\/mTOR phosphorylation. An insulin reactivation (\u201crescue\u201d) strategy was used to functionally test pathway dependence. Transcriptome-derived candidates were further examined by RT\u2013qPCR and STEAP2 overexpression to probe node-level involvement. In addition, molecular docking and 100-ns molecular dynamics simulations were performed to characterize ligand\u2013target binding stability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Ginkgetin suppressed bladder cancer cell viability in a time- and dose-dependent manner at low micromolar concentrations, while normal urothelial cells required markedly higher exposures. Functionally, ginkgetin reduced clonogenic survival, inhibited migration, and shifted EMT features toward an epithelial phenotype. Apoptosis increased in parallel, accompanied by a pro-apoptotic protein signature. Multi-omics and network analyses converged on PI3K\u2013Akt signaling, and experimental validation showed that ginkgetin primarily dampened pathway output by reducing PI3K\/AKT\/mTOR phosphorylation rather than total protein abundance. Insulin-mediated reactivation partially reversed phosphorylation suppression and attenuated apoptosis-related shifts, supporting a functional link between axis inactivation and apoptotic tendency. STEAP2 was consistently downregulated after treatment, and STEAP2 overexpression partially counteracted apoptosis-associated changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support a coherent \u201cphenotype\u2013pathway\u2013node\u201d model in which ginkgetin inhibits malignant phenotypes and promotes apoptosis in bladder cancer cells, associated with reduced PI3K\/AKT\/mTOR activity and STEAP2 downregulation. The PI3K\/AKT\/mTOR axis and STEAP2 emerge as testable mechanistic entry points for further translational validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s41065-026-00686-7","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T08:44:54Z","timestamp":1777625094000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["STEAP2-associated modulation of PI3K\/AKT\/mTOR signaling contributes to ginkgetin-induced apoptosis in bladder cancer cells"],"prefix":"10.1186","volume":"163","author":[{"given":"Pengze","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengkang","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaowen","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilin","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"686_CR1","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.eururo.2025.02.019","volume":"87","author":"AG Van Der Heijden","year":"2025","unstructured":"Van Der Heijden AG, Bruins HM, Carrion A, Cathomas R, Comp\u00e9rat E, Dimitropoulos K, Efstathiou JA, Fietkau R, Kailavasan M, Lorch A, et al. 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