Targeting the SIN1 mediated TTK/LDHA-H3K18la-GLUT3 axis disrupts metabolic-epigenetic crosstalk and suppresses progression in hyperglycolytic breast cancer.

Metabolic-epigenetic crosstalk accelerates breast cancer (BC) progression; however, the conduit linking glycolytic flux to chromatin remodeling remains incompletely defined. Here, we delineate a kinase-metabolism-epigenetic axis centered on the Mitogen-Activated Protein Kinase Associated Protein 1 (MAPKAP1, also known as SIN1). Single-cell transcriptomic profiling of highly invasive tumors identifies SIN1 as a central node co-enriched with epithelial-mesenchymal transition and proliferation programs. Biochemical mapping and mass spectrometry demonstrate that SIN1 scaffolds TTK to promote phosphorylation of lactate dehydrogenase A (LDHA) at Tyr239 (p-LDHA^239), thereby amplifying glycolysis and lactate production. The resulting lactate accumulation increases histone H3K18 lactylation (H3K18la), which, as shown by ChIP-seq, is enriched at the Solute Carrier Family 2 Member 3 (SLC2A3, also known as GLUT3) promoter, upregulating GLUT3 and enhancing glucose uptake, thus establishing a self-reinforcing SIN1/TTK/LDHA-H3K18la-GLUT3 feed-forward loop. Structure-function analyses using domain truncations, molecular docking, and high-throughput virtual screening nominate LR-90 as a small-molecule inhibitor of the SIN1/TTK/LDHA complex. LR-90 reduces p-LDHA^239, lactate levels, H3K18la occupancy at the GLUT3 promoter, glucose uptake, invasion, and tumor growth, and it synergizes with standard chemotherapy in patient-derived organoids and mouse xenografts. Clinically, elevated SIN1 expression is associated with adverse pathological features and inferior overall survival. Collectively, these findings link SIN1-mediated recruitment of TTK for LDHA phosphorylation to histone lactylation and GLUT3-driven metabolic reprogramming, and suggest that pharmacological disruption of this axis with LR-90, alone or in combination with standard chemotherapy, may offer a therapeutic strategy for high-glycolytic, high-lactate breast cancer.