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Here, we found that the FA transporter CD36 was upregulated in myofibroblastic cancer\u2010associated fibroblasts (myoCAFs), where it correlated with the metastasis of oral squamous cell carcinoma (OSCC). Among five predominant FA species enriched in OSCC tissues, palmitic acid (PA) potently activated myoCAF phenotypes across 2D, 3D, and organoid co\u2010culture models. In vivo, PA promoted lymph node metastasis in orthotopic tumors comprising OSCC cells and CAFs, an effect abolished by\n                    <jats:italic>CD36<\/jats:italic>\n                    knockdown in cancer\u2010associated fibroblasts (CAFs). Mechanistically, PA remodeled the chromatin landscape to enhance H3K27ac occupancy at multiple genes including\n                    <jats:italic>ERN1<\/jats:italic>\n                    and\n                    <jats:italic>TMBIM6<\/jats:italic>\n                    , two stress\u2010adaptive regulators. Transcription of\n                    <jats:italic>ERN1<\/jats:italic>\n                    and\n                    <jats:italic>TMBIM6<\/jats:italic>\n                    in CAFs was regulated by CCAAT\/enhancer\u2010binding protein \u03b3 (CEBPG) in an enhancer\u2010associated manner. Disruption of the CEBPG\u2010IRE1\u03b1\/TMBIM6 axis attenuated myoCAFs properties and abrogated PA\u2010driven metastasis. Our results unveil a stromal metabolic checkpoint and establish CEBPG\u2010mediated stress resilience as a therapeutic target to curtail metastasis.\n                  <\/jats:p>\n                  <jats:p>Significance: Palmitic acid promotes metastasis via a stromal CEBPG\u2010IRE1\u03b1\/TMBIM6 axis, uncovering a metabolic vulnerability that offers novel therapeutic targets to inhibit oral squamous cell carcinoma.<\/jats:p>","DOI":"10.1002\/advs.75875","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T14:29:21Z","timestamp":1780410561000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CEBPG\u2010Mediated Palmitic Acid Adaptation of Cancer\u2010Associated Fibroblasts Drives Metastasis of Oral Squamous Cell Carcinoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Yiling","family":"Duan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Hubei Key Laboratory of Stomatology Key Laboratory of Oral Biomedicine Ministry of Education School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Hubei Key Laboratory of Stomatology Key Laboratory of Oral Biomedicine Ministry of Education School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Hubei Key Laboratory of Stomatology Key Laboratory of Oral Biomedicine Ministry of Education School &amp; Hospital of Stomatology Wuhan University  Wuhan 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Stomatology Key Laboratory of Oral Biomedicine Ministry of Education School &amp; Hospital of Stomatology Wuhan University  Wuhan China"},{"name":"Department of Oral and Maxillofacial\u2010Head and Neck Oncology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengjun","family":"Shang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Hubei Key Laboratory of Stomatology Key Laboratory of Oral Biomedicine Ministry of Education School &amp; Hospital of Stomatology Wuhan University  Wuhan China"},{"name":"Department of Oral and Maxillofacial\u2010Head and Neck Oncology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"},{"name":"Taikang Center for Life and Medical Sciences Wuhan University  Wuhan 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