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While SMAD4\u2019s canonical functions within TGF-\u03b2 signaling are well-established, its non-canonical, TGF-\u03b2-independent roles remain poorly understood, particularly in the context of disease biology. Here, we investigate SMAD4\u2019s TGF-\u03b2-independent functions by identifying and characterizing its protein\u2013protein interaction network. Using pancreatic ductal adenocarcinoma as a model system, we performed a SMAD4-focused oncogenic protein\u2013protein interaction mapping and uncovered a novel interaction between SMAD4 and NFATc1. We demonstrated that SMAD4 binds to NFATc1 in a phosphorylation-dependent but TGF-\u03b2-independent manner, sequestering NFATc1 in the cytoplasm and inhibiting its transcriptional activity. The absence of this interaction in SMAD4-deficient PDAC cells is associated with the activation of NFATc1 transcriptional programs and upregulation of STAT3 at both mRNA and protein levels. Pharmacological profiling revealed multiple STAT3 inhibitors with selective efficacy against SMAD4-deficient PDAC cells in vitro, highlighting a potential therapeutic vulnerability. These findings identify a previously uncharacterized SMAD4\u2013NFATc1 regulatory complex and establish its biological significance in regulating NFATc1-driven transcriptional programs, such as STAT3, providing critical insights into SMAD4\u2019s TGF-\u03b2-independent functions and uncovering new opportunities for therapeutic intervention in SMAD4-deficient contexts.<\/jats:p>","DOI":"10.1093\/jmcb\/mjaf028","type":"journal-article","created":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T11:31:17Z","timestamp":1756035077000},"source":"Crossref","is-referenced-by-count":5,"title":["Identification and characterization of a TGF-\n                    <b>\u03b2<\/b>\n                    -independent SMAD4\u2013NFATc1\u2013STAT3 regulatory axis"],"prefix":"10.1093","volume":"17","author":[{"given":"Wukun","family":"Ouyang","sequence":"first","affiliation":[{"name":"Emory University Department of Pharmacology and Chemical Biology, School of Medicine, Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaying","family":"Hao","sequence":"additional","affiliation":[{"name":"Emory University Department of Pharmacology and Chemical Biology, School of Medicine, Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiankun","family":"Niu","sequence":"additional","affiliation":[{"name":"Emory University Department of Pharmacology and Chemical Biology, School of Medicine, Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Eugene F","family":"Douglass","sequence":"additional","affiliation":[{"name":"University of Georgia Department of Pharmaceutical and Biomedical Sciences, , Athens, GA 30602 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M","family":"Beusch","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine Department of Pathology and Laboratory Medicine, , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E","family":"Gordon","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine Department of Pathology and Laboratory Medicine, , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Hall","sequence":"additional","affiliation":[{"name":"Emory University Department of Hematology and Medical Oncology, , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Moffitt","sequence":"additional","affiliation":[{"name":"Emory University Department of Hematology and Medical Oncology, , Atlanta, GA 30322 ,","place":["USA"]},{"name":"Emory University Department of Biomedical Informatics, , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Du","sequence":"additional","affiliation":[{"name":"Emory University Department of Pharmacology and Chemical Biology, School of Medicine, Atlanta, GA 30322 ,","place":["USA"]},{"name":"Emory Chemical Biology Discovery Center, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiulei","family":"Mo","sequence":"additional","affiliation":[{"name":"Emory University Department of Pharmacology and Chemical Biology, School of Medicine, Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"2026021123420073200_bib1","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/ng.3593","article-title":"Functional characterization of somatic mutations in cancer using network-based inference of protein activity","volume":"48","author":"Alvarez","year":"2016","journal-title":"Nat. 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