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However, the mechanisms through which its interacting partners modulate p53 transcriptional activity remain poorly understood. In this study, we identified the transcription factor FOXN3 as a key partner that recruits p53 for transcriptional responses. FOXN3 directly interacts with p53, and the two factors exhibit extensive genome\u2010wide colocalization in both lung cancer cells and clinical tumor tissues, thereby co\u2010regulating the transcription of numerous genes. Notably, nearly all p53 point mutants with disrupted DNA\u2010binding capacity show markedly reduced association with FOXN3, underscoring the essential role of FOXN3 in facilitating p53 binding to DNA. Conditional knockout of FOXN3 promotes lung cancer cell survival, invasion, and tumorigenesis. Importantly, the regulation of p53 transcriptional activity by FOXN3 requires phosphorylation at the S83 and S85 sites. This phosphorylation induces the dissociation of FOXN3 from chromatin, thereby inhibiting p53 transcriptional recruitment and activation. Ablation of FOXN3 S83 and S85 phosphorylation impedes the progression of LUAD. Furthermore, increased phosphorylation of FOXN3 at S83 and S85 is observed in clinical lung tumor tissues and correlates with poor prognosis in patients with LUAD, highlighting its potential as a therapeutic target.<\/jats:p>","DOI":"10.1002\/advs.76449","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:41:14Z","timestamp":1783420874000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulation of Lung Adenocarcinoma by Phosphorylated FOXN3\u2010Mediated Transcriptional Inactivation of p53"],"prefix":"10.1002","volume":"13","author":[{"given":"Jinjin","family":"Yu","sequence":"first","affiliation":[{"name":"Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease Department of Respiratory and Critical Care Medicine First Affiliated Hospital Bengbu Medical University  Bengbu China"},{"name":"Molecular Diagnosis Center Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Yu","sequence":"additional","affiliation":[{"name":"Research Center of Clinical Laboratory Science School of Laboratory Medicine Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease Department of Respiratory and Critical Care Medicine First Affiliated Hospital Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghong","family":"Hu","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease Department of Respiratory and Critical Care Medicine First Affiliated Hospital Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lele","family":"Jin","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease Department of Respiratory and Critical Care Medicine First Affiliated Hospital Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Molecular Diagnosis Center Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Ni","sequence":"additional","affiliation":[{"name":"Molecular Diagnosis Center Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease Department of Respiratory and Critical Care Medicine First Affiliated Hospital Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengling","family":"Zhao","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease Department of Respiratory and Critical Care Medicine First Affiliated Hospital Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Research Center of Clinical Laboratory Science School of Laboratory Medicine Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease Department of Respiratory and Critical Care Medicine First Affiliated Hospital Bengbu Medical University  Bengbu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baofa","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology Frontiers Science Center For Cell Responses College of Life Sciences Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxing","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Psychology Xinxiang Medical University  Xinxiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunfu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Microbiology Immunology &amp; 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