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Here, we identify palmitoylation as a previously unrecognized post\u2010translational modification of SMAD4. Combining biochemical labeling, mutagenesis, and functional assays, we demonstrate that SMAD4 is palmitoylated at cysteine 363 by the acyltransferase ZDHHC22 and depalmitoylated by APT2. Mechanistically, palmitoylation enhances SMAD4 protein stability, facilitates the interaction of SMAD4 with importins, and amplifies subsequent transcriptional output, leading to direct upregulation of the key fatty acid biosynthetic enzyme FASN. Consequently, elevated palmitic acid levels in turn reinforce SMAD4 palmitoylation, establishing a self\u2010amplifying SMAD4 palmitoylation\u2013FASN\u2013palmitic acid positive feedback loop that drives PDAC tumor growth. Intriguingly, SMAD4 palmitoylation\u00a0sensitizes PDAC cells to radiotherapy both in vitro and in vivo, revealing a dual role between tumor progression and treatment responses. Notably, clinically relevant SMAD4 mutants (R361C and R361H) exhibit enhanced palmitoylation, underscoring the pathological relevance of this mechanism for tumorigenesis. Collectively, these findings unveil a metabolic\u2010transcriptional circuit wherein palmitoylation bridges lipid metabolism with SMAD4\u2010driven oncogenesis, and posit SMAD4 palmitoylation as a therapeutic vulnerability in pancreatic cancer.\n                  <\/jats:p>","DOI":"10.1002\/advs.202519791","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T12:42:47Z","timestamp":1774528967000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SMAD4 Palmitoylation Drives a Metabolic\u2010Transcriptional Circuit to Promote Tumorigenesis and Confers Radiosensitivity in Pancreatic Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2204-6053","authenticated-orcid":false,"given":"Yang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Shanghai Tenth People's Hospital Tongji University School of Medicine  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