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While the Cell Division Cycle 6 (CDC6) protein has been extensively characterized across multiple cancer types, its functional role in the pathogenesis of pancreatic cancer remains poorly understood. In this study, we performed bioinformatics analysis using RNA-seq data from The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma cohort, and identified differentially expressed genes through microarray profiling. We conducted a comprehensive functional characterization of CDC6 using CCK-8, colony formation, wound healing, Transwell assays, and flow cytometry, and assessed cellular glycolysis levels based on measurements of ATP production, lactic acid generation, and glucose content. Subcutaneous xenograft mouse models were established to evaluate the impact of CDC6 on tumor growth in vivo, while mechanistic investigations were carried out using co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter assays, and nucleocytoplasmic fractionation. Our results revealed that CDC6 expression is upregulated in pancreatic cancer, and its elevated expression is significantly correlated with unfavorable patient prognosis. Functional experiments demonstrated that CDC6 promotes the proliferation, migration, and invasion of pancreatic cancer cells. Thrombospondin 1 (THBS1) was identified to be positively correlated with CDC6 expression, and differentially expressed genes were notably enriched in the glucose metabolism pathway. Mechanistically, CDC6 cooperates with E2F1 to facilitate the transcription of THBS1, and the AKT signaling pathway is activated via the CDC6\/THBS1 interaction. Overexpression of CDC6 significantly promoted glycolysis and tumor progression in pancreatic cancer, whereas these pro-tumor effects were markedly abrogated by THBS1 knockdown. Collectively, our findings demonstrate that CDC6\/THBS1\/AKT signaling drives glycolysis and accelerates pancreatic cancer progression, suggesting that the CDC6\/THBS1\/AKT axis may serve as a promising therapeutic target for pancreatic cancer.<\/jats:p>","DOI":"10.1038\/s41419-026-08758-2","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T08:22:30Z","timestamp":1776759750000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CDC6\/THBS1 accelerates pancreatic cancer progression via AKT-mediated glycolytic reprogramming"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4840-6670","authenticated-orcid":false,"given":"Mengqiu","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0136-1150","authenticated-orcid":false,"given":"Jinhui","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"8758_CR1","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.2217\/fon-2021-0483","volume":"18","author":"BP Venkatesulu","year":"2022","unstructured":"Venkatesulu BP, Chan DP, Giridhar P, Upadhyay R, Sharma A, Elghazawy H, et al. 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All animal experiments have been approved by the Experimental Animal Welfare and Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (approval number: AIRB-2022-0070). The ethics committee made a statement regarding the animal experiment project it had approved: The maximum tumor volume allowed for the experimental subjects enrolled in this study and during the entire duration of the experiment is 2000 mm\u00b3. We confirm that informed consent was obtained from all subjects and all experiments were conducted in accordance with the guidelines and rules of the committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"ETHICS"}}],"article-number":"524"}}