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RPRD1B (CREPT), a gene frequently overexpressed in GC, has been clinically associated with advanced tumor stage and poor prognosis. Functionally, RPRD1B promotes aggressive tumorigenic phenotypes by accelerating cell-cycle progression, potentiating proliferative signaling, and enhancing the migratory and invasive capacities of cancer cells. However, its functional role in mediating chemotherapy resistance has not been elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established 5-FU-resistant gastric cancer cell lines (from AGS\/MGC803 parents via stepwise drug exposure) to study RPRD1B\u2019s mechanism, and developed an AAV-based system to therapeutically target RPRD1B to overcome 5-FU resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, we demonstrated that GC patients with high tumor expression of RPRD1B (CREPT) exhibited a poor response to 5-fluorouracil (5-FU)-based chemotherapy. Furthermore, RPRD1B expression was positively correlated with the expression of TOPBP1, a critical DNA damage response and repair effector. Mechanistically, RPRD1B transcriptionally upregulates TOPBP1 by recruiting RNA polymerase II to its promoter, thereby enhancing DNA damage repair. Using an AAV-delivered shRNA to knockdown RPRD1B in a nude mouse xenograft model, we effectively overcame 5-FU resistance in gastric tumors in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identify RPRD1B as a promising therapeutic target for reversing chemoresistance in gastric cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s13402-026-01227-0","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T22:04:40Z","timestamp":1785621880000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting RPRD1B overcomes chemoresistance in gastric cancer by suppressing the TOPBP1-mediated DNA damage repair pathway"],"prefix":"10.1007","volume":"49","author":[{"given":"Jian","family":"Sheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaorong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjian","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangli","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chundong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahui","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"1227_CR1","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1007\/s10120-020-01104-1","volume":"24","author":"S Kinami","year":"2021","unstructured":"S. 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