Abstract
Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, with limited therapeutic options and dismal prognosis. Histone methyltransferase NSD2 and its catalytic product H3K36me2 are established drivers of TNBC metastasis; however, the downstream effectors linking epigenetic regulation to cellular senescence remain largely unknown. This study utilized transcriptomic profiling, ChIP-qPCR, and in vivo xenograft models to define the function and molecular mechanism of the NSD2-ATAD3A axis. We found that NSD2 was upregulated in metastatic TNBC and associated with worse survival. NSD2 directly activated ATAD3A transcription via H3K36me2 enrichment at the ATAD3A promoter. The NSD2-ATAD3A axis interacted with Drp1, triggering mitochondrial fragmentation, respiratory chain dysfunction, and lactate accumulation. Elevated lactate further induced HMGB1 lactylation and enhanced its protein stability, which sequentially activated senescence-associated genes and the senescence-associated secretory phenotype (SASP), consequently promoting epithelial-mesenchymal transition (EMT) and tumor progression. The NSD2 inhibitor KTX-1001 combined with ATAD3A knockdown enhanced the suppression of tumor burden and invasive potential with favorable biosafety.enhancedenhanced This study identifies a novel NSD2-H3K36me2-ATAD3A-Drp1-HMGB1 lactylation axis that drives senescence-associated progression in TNBC, providing a promising epigenetic-metabolic combination therapeutic strategy for this disease.