O-GlcNAcylation of NSD2 Promotes Lung Metastasis of Triple-Negative Breast Cancer through Extracellular Matrix Remodeling

Metastasis is the leading cause of treatment failure and poor prognosis in triple-negative breast cancer (TNBC), underscoring the urgent need for effective therapeutic strategies. In this study, we show that O-GlcNAcylation catalyzed by O-GlcNAc transferase (OGT) increases NSD2 stability and thereby promotes TNBC metastasis. Mechanistically, OGT directly interacts with NSD2 and facilitates its O-GlcNAcylation, which impedes ubiquitin-mediated degradation and enhances NSD2 protein stability. OGT knockdown reduces NSD2 protein levels, downregulates extracellular matrix (ECM)-related signaling pathways, decreases collagen production and cell–matrix adhesion, and ultimately inhibits TNBC cell invasion and tumor metastasis. Importantly, disruption of the OGT–NSD2 axis markedly suppresses metastasis in TNBC xenograft models. Together, these findings reveal a novel mechanism by which OGT drives tumor metastasis through modulation of NSD2 O-GlcNAcylation, and identify the OGT–NSD2 axis as a potential therapeutic target for advanced TNBC.