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The cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) is a critical enzyme in acetaldehyde metabolism, but the interconnection to the basal-like subtype is poorly understood. Here, we identified ALDH1A3 as a key gene, which correlates with reduced survival and increased tumor growth. Functional studies revealed interaction of ALDH1A3 with genes like FAM3C, MCC, PMEPA1, and IRS2, forming a network driving PDAC progression. Chromatin profiling showed that ALDH1A3 affects acetylation of histone 3, mediating AP-1 activity, particularly via FOS family members, activating oncogenic pathways such as MAPK and TNF signaling. RUNX2 emerged as a therapeutic target within this network, as its knockdown disrupted MAPK signaling and reduced tumor growth. These findings emphasize the role of ALDH1A3 in linking nuclear metabolic-epigenetic programming in basal-like PDAC, highlighting it as a promising therapeutic target for novel treatment strategies.<\/jats:p>","DOI":"10.1038\/s41388-025-03530-w","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T18:33:48Z","timestamp":1754678028000},"page":"3774-3786","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ALDH1A3 promotes aggressive basal-like pancreatic cancer through an AP-1\/RUNX2 enhancer 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All mouse experiments and procedures were approved by the Institutional Animal Care and Use Committee of the Technical University of Munich (approval numbers: 55.2-1-54-2532-197-2016, ROB-55.2-2532.Vet_02-17-83), which address the ARRIVE guidelines. All procedures involving transgenic mice were performed in accordance with the Office of Laboratory Animal Welfare and German Federal Animal Protection Laws. BALB\/c nu\/nu athymic mice were approved by the Animal Care and Use Committee of the Nanjing Drum Tower Hospital (approval number: 20180102). All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}]}}