The metabolic and post-translational modification results generated in the first two years of KetoCardio provide a solid mechanistic foundation with clear translational potential. By defining how ketone metabolism is altered in HFpEF and generating the first cardiac β-hydroxybutyrylation (Kbhb) atlas in this setting, the project begins to reshape the conceptual understanding of cardiometabolic heart failure. The work shows that ketone handling is a central determinant of energetic homeostasis in HFpEF, with direct implications for substrate competition, nutritional and metabolic interventions, and patient phenotyping. These findings offer a mechanistic rationale for targeting ketone pathways therapeutically and for interpreting shifts in fuel hierarchy as contributors to disease progression. Equally significant is the demonstration that Kbhb acts as a regulatory layer in the failing heart. The Kbhb proteomic landscape highlights extensive modification of mitochondrial and metabolic enzymes, expanding the role of β-hydroxybutyrate far beyond chromatin regulation. This establishes a framework for studying PTM-mediated control of mitochondrial function, identifying biomarkers of metabolic stress, and integrating PTMs into systems-level models of HFpEF progression. The accompanying chromatin data suggest that ketone-sensitive PTMs also influence transcriptional programs that shape cardiomyocyte stress adaptation. By linking ketone flux, PTM distribution, and enzymatic function, the project identifies specific molecular nodes that may be exploited therapeutically. These mechanistic insights support the development of modulators of PTM-regulated enzymes, strategies to manipulate ketone availability or oxidation, and refined models for stratifying HFpEF patients according to metabolic signatures. Together, these advances position KetoCardio to influence both cardiac metabolism research and the broader field of metabolic signalling. To enable full uptake of these insights, further work is needed to define causality through targeted perturbation of Kbhb-modified enzymes and chromatin marks, in vivo modulation of ketone levels, and deeper integration of liver–heart metabolic interactions. Progress will also depend on expanding proteomic depth, integrating additional PTMs, and refining metabolic modelling frameworks. Although commercialisation remains premature, the project has already begun to generate assets with potential diagnostic or therapeutic value, such as PTM signatures, enzyme targets, and novel assays for Kbhb detection.
