Objective:?Triple-negative breast cancer (TNBC), a clinically aggressive subtype characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, exhibits intrinsic therapeutic resistance and a propensity for rapid progression. TNBC displays unique metabolic reprogramming marked by heightened glycolytic dependence, manifested through upregulation of glycolytic enzymes and glucose transporters, augmented glucose uptake, and excessive lactate secretion. Emerging evidence suggests that the lactate-enriched tumor microenvironment may drive malignant progression, although the precise molecular mechanisms remain incompletely understood. The transcriptional coactivator EP300 (E1A-binding protein p300), which possesses histone acetyltransferase activity, serves as a critical epigenetic mediator by coupling metabolic cues with transcriptional regulation through post-translational modifications such as acetylation and lactylation. Mechanistically, lactate-induced histone lactylation facilitates EP300 recruitment to oncogenic promoters (e.g., HIF-1α, MYC), thereby activating proliferation- and metastasis-associated signaling pathways. This study elucidates the functional impact of lactate on TNBC malignancy and unveils an m6A-dependent epigenetic mechanism through which insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) orchestrates metabolic reprogramming via regulation of EP300.Methods:?TNBC cells were treated with exogenous sodium lactate supplementation to investigate its oncogenic effects. Cellular proliferative capacity was systematically assessed using CCK-8 assay, while clonogenic potential was evaluated through colony formation analysis. Two-dimensional migration dynamics were quantified via scratch wound healing assay, and three-dimensional invasive potential was determined using Transwell chambers. To establish IGF2BP3-knockdown models, lentiviral-delivered shRNA constructs were employed for stable gene silencing. Histone lactylation modification levels were analyzed by Western blotting. Genome-wide identification of IGF2BP3-associated m6A targets was performed through RNA immunoprecipitation sequencing (RIP-seq) and m6A-specific methylated RNA immunoprecipitation sequencing (MeRIP-seq). Key regulatory molecules were validated at transcriptional and protein levels using quantitative reverse transcription PCR (qRT-PCR) and Western blotting, respectively.Results: Sodium lactate treatment potentiated TNBC cell proliferation and migratory capacity, with pan-lactylation levels exhibiting concentration-dependent augmentation. Mechanistic interrogation revealed that IGF2BP3 depletion markedly attenuated histone lactylation modifications. Integrative analysis of RIP-seq and MeRIP-seq datasets identified 699 candidate genes whose transcripts were both specifically bound by IGF2BP3 and harbored m6A modifications. Pathway enrichment analysis demonstrated significant association of these genes with epigenetic regulation and metabolic pathways. Spatial mapping identified substantial overlap between IGF2BP3-binding regions and m6A modification sites on EP300 transcripts. Functional validation confirmed significant downregulation of EP300 expression at transcriptional and protein levels following IGF2BP3 knockdown.Conclusion: Exogenous lactate drives TNBC malignant progression by orchestrating pan-lactylation modifications. Mechanistically, IGF2BP3 governs EP300 expression through m6A-dependent post-transcriptional regulation, thereby mediating a synergistic interplay between histone lactylation and metabolic reprogramming that ultimately propels tumor progression. These findings lay the mechanistic foundation for developing innovative therapeutic strategies targeting the metabolic-epigenetic crosstalk in TNBC.