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However, the modulation of SREBP-1 transcriptional activity remains incompletely understood. Here, we report that the transcription factor FOXN3 interacts with the KU70\/KU80\/SREBP-1 complex, facilitating the recruitment of SREBP-1 for the transcriptional activation of lipogenic response genes. Hepatocyte-specific knockout of FOXN3 significantly alleviates the pathological progression of NAFLD by suppressing fatty acid and cholesterol synthesis. Furthermore, phosphorylation of FOXN3 at the S83 and S85 residues disrupts the stability of the KU70\/KU80\/FOXN3\/SREBP-1 complex, which is required for SREBP-1 transcriptional activity. This disruption consequently impedes the progression of NAFLD. Clinical investigations reveal that FOXN3, KU80, and SREBP-1 co-target the promoters of lipogenic response genes in fatty liver tissues from patients. Notably, phosphorylation levels of FOXN3 at S83 and S85 are significantly reduced in fatty liver tissues compared to normal samples. This reduction enhances the enrichment of the FOXN3\/SREBP-1 complex at the promoters of lipogenic response genes during the progression of NAFLD. Our study underscores the critical role of FOXN3 in maintaining the intact KU70\/KU80\/FOXN3\/SREBP-1 complex, which is essential for SREBP-1-mediated metabolic disorders.<\/jats:p>","DOI":"10.1093\/nar\/gkag171","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T10:17:59Z","timestamp":1772273879000},"source":"Crossref","is-referenced-by-count":14,"title":["FOXN3 integrates the KU70\/KU80\/SREBP-1 complex to regulate lipid metabolism in non-alcoholic fatty liver disease"],"prefix":"10.1093","volume":"54","author":[{"given":"Jiang","family":"Du","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 233004 ,","place":["China"]},{"name":"Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University , Xinxiang 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First Affiliated Hospital, Bengbu Medical University , Bengbu 233004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjin","family":"Yu","sequence":"additional","affiliation":[{"name":"Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University , Bengbu 233004 ,","place":["China"]},{"name":"Regenerative Medicine Sciences Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia , Kepala Batas 13200 ,","place":["Malaysia"]}],"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 233004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyang","family":"Huo","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 233004 ,","place":["China"]},{"name":"Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University , Xinxiang 453003 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University , Bengbu 233004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Liu","sequence":"additional","affiliation":[{"name":"Research Center of Clinical Laboratory Science, School of Laboratory Medicine, Bengbu Medical University , Bengbu 233004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University , Bengbu 233004 ,","place":["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 233004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8331-1933","authenticated-orcid":false,"given":"Sizhou","family":"Huang","sequence":"additional","affiliation":[{"name":"Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College , Chengdu 610500 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