A ß-Hydroxybutyrylation–FOXM1/CENPA Axis Links Ketone-Body Metabolism to Mitotic Transcription in Triple-Negative Breast Cancer

Lysine β-hydroxybutyrylation (Kbhb) is a metabolite-derived post-translational modification of histone and non-histone proteins that couples β-hydroxybutyrate (BHB) availability to gene expression. Yet the transcription factors that govern the Kbhb substrate program in cancer remain unidentified. Existing studies have cataloged Kbhb-modified substrates or examined individual proteins, without identifying the transcriptional regulators of the program in a defined tumor context. Here, we performed network-based Master Regulator Analysis (MRA), implemented in the viper package, on a molecular signature restricted to experimentally validated Kbhb substrates, across two independent Basal-like breast cancer cohorts profiled on orthogonal platforms: TCGA-BRCA (RNA-seq; n = 195 tumor, 113 normal) and METABRIC (microarray; n = 209 tumor, 148 normal). Dataset-specific regulatory networks were inferred with ARACNe-AP and integrated by cross-platform Stouffer meta-analysis. Of 1,493 Kbhb substrates, 1,322 and 1,213 were expressed in the respective cohorts. The analysis identified seven concordant transcriptional master regulators (six activated, one repressed; cross-cohort NES correlation r = 0.64), with CENPA (meta-NES +4.55) and FOXM1 (meta-NES +4.27) as the dominant drivers. These findings nominate a BHB–Kbhb–FOXM1/CENPA axis linking ketone-body metabolism to mitotic transcription, with potentially protumoral implications for ketogenic regimens in triple-negative breast cancer.