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Pancreatic ductal adenocarcinoma (PDAC), a poorly differentiated and highly aggressive tumor, has a poor prognosis, whereas well-differentiated tumors often correlate with better outcomes. The mechanisms underlying differentiation and its therapeutic potential remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study aims to investigate whether inducing transdifferentiation in pancreatic cancer cells can reduce malignancy, focusing on the role of the transcription factor NeuroD1 and its regulatory pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed single-cell RNA-seq data from the GEO database to identify differentiation-associated genes. NeuroD1 was overexpressed in PDAC cells to assess its effects on transdifferentiation and proliferation. Drug screening and molecular docking were performed to identify differentiation-inducing compounds. RNA sequencing, coimmunoprecipitation, and mass spectrometry were used to identify NeuroD1-interacting proteins. Cell\/patient-derived xenograft mouse models are utilized for in vivo experiments and compound efficacy testing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Highly differentiated tumor cells exhibited elevated NeuroD1 expression. NeuroD1 overexpression promoted neuronal transdifferentiation and suppressed proliferation. Neuropathiazol, a neurogenic inducer, was found to bind MET and upregulate NeuroD1 via the PI3K\/Akt pathway, enhancing transdifferentiation and inhibiting tumor growth. Neurog3 was identified as a functional partner of NeuroD1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate that pancreatic cancer cells can be induced to transdifferentiate through NeuroD1 activation or pharmacological induction, suggesting a potential therapeutic strategy to mitigate malignancy by reprogramming tumor cells into less aggressive states.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03563-9","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T15:17:56Z","timestamp":1762960676000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neurogenic inducers inhibit the proliferation of pancreatic cancer by promoting tumor cell transdifferentiation"],"prefix":"10.1186","volume":"44","author":[{"given":"Duancheng","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saimeng","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longyun","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxia","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinglin","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaizhou","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xichun","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiding","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"issue":"3","key":"3563_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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