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The diagnostic and treatment limitations have resulted in great challenges in improving the survival of patients with PDAC. Ubiquitination is an indispensable posttranslational modification involved in all cellular processes via proteolytic or nonproteolytic pathways. Deubiquitinating enzymes (DUBs) comprise ~100 proteases that remove ubiquitin from targeted proteins to regulate cellular physiological or pathological processes. Accumulating evidence has shown that DUBs are involved in the regulation of the occurrence and development of cancers. Currently, a substantial number of studies have reported that DUBs are involved in the malignant progression of PDAC. Hence, we summarize and review the latest research advances in understanding the mechanism by which DUBs are involved in modulating the development of PDAC, including proliferation, migration, invasion, metastasis, metabolic reprogramming, and chemoresistance. In addition, we present studies on how DUBs affect the immune microenvironment of PDAC and briefly characterize some therapeutic perspectives of PDAC that ultimately depend on the targeting of DUBs.<\/jats:p>","DOI":"10.1038\/s41419-025-08052-7","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T13:41:57Z","timestamp":1760622117000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The multifaceted roles of deubiquitinating enzymes (DUBs) in pancreatic ductal adenocarcinoma"],"prefix":"10.1038","volume":"16","author":[{"given":"Min","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongtian","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangbing","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9744-7201","authenticated-orcid":false,"given":"Jun","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1654-1285","authenticated-orcid":false,"given":"Renyi","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5664-7757","authenticated-orcid":false,"given":"Min","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"8052_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2021.102180","volume":"96","author":"S De Dosso","year":"2021","unstructured":"De Dosso S, Siebenhuner AR, Winder T, Meisel A, Fritsch R, Astaras C, et al. 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