SATB2 Mediates H3K9 Delactylation by Recruiting HDAC3 to Repress LCN2 and Inhibit Lung Tumor Growth and Metastasis

ABSTRACT Lung cancer remains a leading cause for global cancer‐related mortality, with therapeutic resistance and metastasis posing major clinical challenges. The special AT‐rich sequence‐binding protein 2 (SATB2) is a well‐established tumor suppressor in NSCLC, but its downstream epigenetic and metabolic regulatory mechanisms remain largely unclear. Here, we demonstrate that SATB2 exerts tumor‐suppressive 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)—a previously uncharacterized histone mark in NSCLC. Through integrated multi‐omics analyses (RNA‐seq and H3K9la‐specific CUT&Tag), we identified Lipocalin‐2 (LCN2), an oncoprotein, as a critical downstream target of the SATB2‐H3K9la axis. SATB2 is able to bind LCN2 promoter and recruit histone deacetylase 3 (HDAC3) via its N‐terminal domain, catalyzing H3K9 delactylation to repress LCN2 transcription. Exogenous lactate reversed SATB2‐mediated 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‐metabolic crosstalk pathway in NSCLC, providing new insights into the molecular mechanisms of SATB2‐mediated tumor suppression and potential therapeutic targets for NSCLC.