RBBP4 orchestrates glycolytic reprogramming and NF-κB-mediated immune evasion in triple-negative breast cancer

Objective: To investigate the role of retinoblastoma binding protein 4 (RBBP4) in triple-negative breast cancer (TNBC), an aggressive tumor lacking targeted treatments, and explore its potential as a therapeutic target. Methods: The study analyzed RBBP4 expression in TNBC tumors and its association with patient survival. Experimental approaches included assessing the impact of RBBP4 on in vitro cellular proliferation and in vivo tumor growth, as well as invasion and migration. Transcriptomic analyses were performed to examine RBBP4-driven metabolic reprogramming. Molecular interactions between RBBP4 and RelB, and the effects of glycolysis-derived lactate on epigenetic regulation, were also investigated. Results: RBBP4 was upregulated in TNBC tumors, with higher levels inversely associated with patient survival. RBBP4 promoted in vitro TNBC cellular proliferation and in vivo tumor growth but had no effect on invasion or migration. Transcriptomic analyses revealed RBBP4-driven reprogramming of glycolytic metabolism, characterized by Warburg effect-related phenotypes (elevated glucose consumption, lactate generation, and extracellular acidification). At the molecular level, RBBP4 interacted with RelB, activating NF-κB, which led to nuclear RelB translocation and PD-L1 upregulation. Additionally, glycolysis-derived lactate induced H3K18 lactylation, forming a feedforward epigenetic loop that sustained RBBP4 expression. Conclusion: RBBP4 acts as a nodal regulator linking metabolic reprogramming, NF-κB activation, and immune evasion in TNBC. Targeting RBBP4 or its associated downstream pathways may offer viable strategies for managing TNBC.