{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T16:34:41Z","timestamp":1781886881637,"version":"3.54.5"},"reference-count":37,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Hospital-level project of Taizhou People\u2019s Hospital","award":["ZL201938"],"award-info":[{"award-number":["ZL201938"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Dose-Response"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Resistance to platinum-based chemotherapy in bladder cancer is closely associated with activation of the Fanconi anemia (FA) DNA interstrand crosslink repair pathway. Identifying pharmacological inhibitors of FA signaling may improve therapeutic response. We investigated the effects of the natural compound toosendanin (TSN) on FA pathway regulation in this study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bladder cancer cell lines (T24, RT4, J82) were pretreated with TSN and exposed to ultraviolet C (UVC). FANCI\/FANCD2 monoubiquitination, FANCD2 nuclear foci, FA core gene expression, and JAK\/STAT1 signaling were quantified. A T24 xenograft model was used to validate FA pathway inhibition in vivo. Statistical analyses were performed using one-way ANOVA followed by Tukey\u2019s post-hoc test (mean \u00b1 SD; n = 3 independent replicates; Shapiro\u2013Wilk test for normality).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TSN reduced UVC-induced 58% FANCI (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.004, n = 3) and 77% FANCD2 monoubiquitination (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.004, n = 3) in bladder cancer cells, and decreased FANCD2 foci-positive nuclei by 27% (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.015, n = 3). Co-immunoprecipitation assays further revealed that TSN disrupted 56% interaction between the FANCI-FANCD2 complex and the key scaffold protein SLX4 (FANCP) (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.002, n = 6). TSN down-regulated FA core genes (FANCA, FANCC, FANCF, FANCM) by 30 to 65% (all\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05, n = 3) as well as decreased STAT1 phosphorylation by 45% (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.013, n = 3) and the binding capacity of STAT1 on these FA genes\u2019 promoter by 33% to 47% (all\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05, n = 3). In xenograft tumors, TSN also reduced 70% FANCI (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.007, n = 3) and 45% FANCD2 monoubiquitination (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.011, n = 3) as well as expression of FANCA, FANCC, FANCF, FANCM by 26% to 38% (all\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05, n = 3). TSN selectively sensitized bladder cancer cells to UVC-induced cytotoxicity (IC50 decreased 35%,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.026, n = 3), without affecting the viability of human urothelial cell SV-HUC-1 cells or lung adenocarcinoma A549 cells (both\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &gt; 0.05, n = 3).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TSN inhibits FA DNA repair signaling in bladder cancer by suppressing JAK\/STAT1-mediated FA core gene transcription, supporting its potential as a combinatorial agent to overcome cisplatin resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15593258251406039","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:33:31Z","timestamp":1764722011000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["TSN Disrupts Fanconi Anemia Pathway Activation Through JAK\/STAT1-Mediated Transcriptional Repression of FA Core Subunits in Bladder Cancer"],"prefix":"10.1177","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6871-7237","authenticated-orcid":false,"given":"Wenchao","family":"Zhao","sequence":"first","affiliation":[{"name":"The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2952-5826","authenticated-orcid":false,"given":"Zhiyuan","family":"Xie","sequence":"additional","affiliation":[{"name":"The Affiliated Taizhou People\u2019s Hospital of Nanjing 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