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Uncovering molecular mechanisms underlying this resistance is essential for developing more effective treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Gemcitabine-resistant GBC cell lines were generated and subjected to transcriptomic sequencing to identify resistance-associated genes. A genome-wide CRISPR-Cas9 knockout screen was used to pinpoint key genetic regulators. Functional validation was performed through gene knockdown and overexpression, cell viability and apoptosis assays, colony formation, and DNA damage analysis. A high-throughput virtual screening (HTVS) approach was applied to identify small-molecule inhibitors targeting the E2F8-DNA interaction. The efficacy of selected compounds was tested in vitro and in xenograft mouse models, and further validated using patient-derived organoids (PDOs) established from primary and recurrent gallbladder cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The transcription factor E2F8 was identified as a driver of gemcitabine resistance via upregulation of RRM2, a gene involved in DNA repair. Knockdown of E2F8 enhanced sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors in resistant GBC cells by impairing DNA repair. HTVS yielded HIT-4, a small-molecule inhibitor that binds to E2F8 and disrupts its interaction with DNA, leading to reduced RRM2 expression. HIT-4 significantly increased apoptosis and DNA damage when combined with PARP inhibitors. In vivo and in PDO models, HIT-4 and PARP inhibitor co-treatment markedly suppressed tumor growth, extended survival, and showed minimal toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identifies the E2F8-RRM2 axis as a key regulator of gemcitabine resistance in GBC and establishes E2F8 as a druggable target. The novel compound HIT-4, in combination with PARP inhibitors, represents a promising therapeutic strategy to overcome chemoresistance and warrants further clinical investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03586-2","type":"journal-article","created":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T22:52:45Z","timestamp":1765752765000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeting E2F8 sensitizes gemcitabine-resistant gallbladder cancer to PARP inhibitors by disrupting RRM2-driven DNA repair"],"prefix":"10.1186","volume":"45","author":[{"given":"Xiaojian","family":"Ni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqing","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichang","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houbao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,14]]},"reference":[{"key":"3586_CR1","first-page":"99","volume":"6","author":"R Hundal","year":"2014","unstructured":"Hundal R, Shaffer EA. 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Informed consent was obtained from all participating patients. All animal experiments were conducted in compliance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Zhongshan Hospital, Fudan University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors consent to publish the paper.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19"}}