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.
Keywords: H3K9 delactylation; HDAC3; LCN2; SATB2; lung cancer.
© 2026 The Author(s). Advanced Science published by Wiley‐VCH GmbH.