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The special AT\u2010rich sequence\u2010binding protein 2 (SATB2) is a well\u2010established tumor suppressor in NSCLC, but its downstream epigenetic and metabolic regulatory mechanisms remain largely unclear. Here, we demonstrate that SATB2 exerts tumor\u2010suppressive effects by impairing NSCLC cell proliferation, migration, invasion, and EMT. Mechanistically, SATB2 functions as a negative regulator of global histone lactylation, with a specific role in reducing histone H3 lysine 9 lactylation (H3K9la)\u2014a previously uncharacterized histone mark in NSCLC. Through integrated multi\u2010omics analyses (RNA\u2010seq and H3K9la\u2010specific CUT&amp;Tag), we identified Lipocalin\u20102 (LCN2), an oncoprotein, as a critical downstream target of the SATB2\u2010H3K9la axis. SATB2 is able to bind LCN2 promoter and recruit histone deacetylase 3 (HDAC3) via its N\u2010terminal domain, catalyzing H3K9 delactylation to repress LCN2 transcription. Exogenous lactate reversed SATB2\u2010mediated H3K9la and LCN2 suppression, restoring oncogenic phenotypes. In vivo, SATB2 overexpression inhibited xenograft tumor growth and lung metastasis, while LCN2 overexpression rescued these suppressive effects. Our findings uncover a novel epigenetic\u2010metabolic crosstalk pathway in NSCLC, providing new insights into the molecular mechanisms of SATB2\u2010mediated tumor suppression and potential therapeutic targets for NSCLC.<\/jats:p>","DOI":"10.1002\/advs.202522996","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T12:21:38Z","timestamp":1772972498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SATB2 Mediates H3K9 Delactylation by Recruiting HDAC3 to Repress LCN2 and Inhibit Lung Tumor Growth and Metastasis"],"prefix":"10.1002","volume":"13","author":[{"given":"Ting","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Genetics School of Basic Medical Sciences Xi'an Jiaotong University  Xi'an Shaanxi 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