β‑Hydroxybutyrate in cancer: context‑dependent metabolic signaling
The review by Wang and Bai examines how β‑hydroxybutyrate (BHB) can act both as an alternative fuel and as a signaling molecule in cancer, highlighting that its effects vary with tumor ketolytic capacity and the cellular composition of the tumor microenvironment.
Study and findings
Wang and Bai synthesize preclinical and limited clinical data on BHB, the main circulating ketone body produced during fasting, prolonged exercise, carbohydrate restriction, and ketogenic dietary regimens. Beyond serving as an oxidative substrate, BHB engages HCAR2 receptors, inhibits histone deacetylases, participates in redox coupling, and modifies proteins through lysine β‑hydroxybutyrylation. The authors identify two mechanistic “switch points” that determine whether BHB exerts anti‑tumor or pro‑tumor actions. First, tumor cells that retain functional ketolytic enzymes (BDH1 and OXCT1) and mitochondrial respiration can oxidize BHB to support growth under nutrient stress. Second, the allocation of BHB within the tumor microenvironment influences whether it fuels malignant cells, supports anti‑tumor lymphocytes, or affects stromal components. The review also stresses that the source of BHB—dietary ketosis, exogenous supplementation, or tumor‑intrinsic ketogenesis—creates distinct experimental conditions that should not be conflated.
Clinical interpretation
The evidence suggests that BHB is not uniformly beneficial or harmful in oncology; its impact is contingent on cellular context. In tumors lacking ketolytic competence, BHB may act primarily as a signaling molecule that suppresses inflammation, angiogenesis, or epithelial‑mesenchymal transition, potentially limiting progression. Conversely, in ketolysis‑competent cancers, BHB can provide an alternative energy source, facilitating metabolic adaptation, survival, and possibly resistance to therapy. Moreover, the distribution of BHB among immune versus malignant cells could modulate anti‑tumor immunity. These nuances imply that any therapeutic strategy involving ketogenic diets or BHB supplementation must consider tumor‑specific metabolic profiling and the immune landscape before anticipating a net effect.
Limitations and open questions
The review relies largely on preclinical models, and direct clinical data linking BHB levels to patient outcomes remain sparse. Heterogeneity in experimental systems—different cancer types, varying degrees of ketolytic enzyme expression, and distinct BHB delivery methods—limits the ability to generalize findings. Critical unanswered questions include: which biomarkers reliably indicate tumor ketolytic capacity; how BHB influences specific immune cell subsets in vivo; and whether controlled modulation of BHB (dietary or pharmacologic) can be integrated safely with standard oncologic therapies. Future investigations need cell‑resolved, longitudinal designs that correlate BHB dynamics with therapeutic response and survival.
Source
Wang Q, Bai Y. β‑Hydroxybutyrate in Cancer: From Alternative Fuel to a Context‑Dependent Metabolic Signal. FASEB J. 2026 Oct 31;doi:10.1096/fj.202603664rr.