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A significant proportion of chemotherapeutics impact DNA replication, yet the mechanisms by which tumors evade this lethality remain incompletely understood. Notably, minichromosome maintenance 10 replication initiation factor (MCM10) is pivotal in initiating DNA replication, holding promise in mediating acquired chemotherapy resistance. This work aims to elucidate the driving roles of MCM10 GC pathogenesis and chemotherapeutic resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The expression pattern of MCM10 and its clinical relevance in GC patients were investigated by adopting single-cell RNA-seq data and in-house GC tissue microarray. Functional roles were evaluated through bioinformatic analyses and experimental assays, including in vivo xenograft formation assay and patient-derived organoid (PDO) models. The transcriptional regulation of MCM10 by the YAP1-TEAD4 complex was examined via\n                      <jats:italic>Yap1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      ;\n                      <jats:italic>Taz<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      transgenic mice models and functional rescue assays. Candidates for targeting MCM10 were predicted by virtual screening and further validated by cellular thermal shift assay (CETSA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MCM10 was the most upregulated MCM family member in GC cell lines, and its elevated levels correlated with poor patient prognosis. Bioinformatic analysis linked MCM10 to DNA replication and DNA damage repair, a finding confirmed by functional assays showing that MCM10 depletion induced DNA damage accumulation and impaired DNA replication. MCM10 was further proven to promote GC cell malignancy and tumorigenesis by activating Wnt\/\u03b2-catenin signaling in GC cell lines, clinical samples, and xenograft models. Critically, MCM10 conferred resistance to chemotherapeutic agents by enhancing cancer cell stemness acquisition and DNA damage response. Mechanistically, YAP1\/TEAD4 was identified as the transcriptional activator of MCM10, as TEAD4 silencing downregulated MCM10. TEAD4 overexpression failed to rescue the tumor-suppressing effects in MCM10-depleted cells. Furthermore, Momordin Ic was identified as a promising MCM10-targeted inhibitor, which effectively attenuated GC cell malignancy and chemoresistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MCM10 drives gastric tumorigenesis by enhancing DNA replication and maintaining cancer stemness, positioning it as a key mediator of YAP1-TEAD4 oncogenic signaling. These findings establish MCM10 as a promising therapeutic target to overcome chemotherapy resistance in GC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-026-02623-8","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T08:17:55Z","timestamp":1772180275000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MCM10, a novel YAP1\/TEAD4 target, drives gastric cancer progression by bridging DNA replication to stemness acquisition"],"prefix":"10.1186","volume":"25","author":[{"given":"Fuda","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoi 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