β-Hydroxybutyrate, a primary metabolite of ketogenic diets and its dual role in modulating colorectal cancer: from molecular mechanisms to therapeutic insights.

Colorectal cancer (CRC) is a genetically varied malignancy noted for its metabolic flexibility, which enables cancer cells to adapt to different energy sources. Beta-hydroxybutyrate (BHB), a significant ketone body that is elevated during ketogenic diets, has attracted considerable attention for its potential therapeutic benefits. ​However, recent evidence indicates that BHB may paradoxically facilitate the advancement of CRC by acting as an alternative energy source, especially in cancer cells with mutations in critical genes such as APC, KRAS, and TP53. This review investigates the mechanisms through which CRC cells utilize BHB for their survival, focusing on enhanced metabolic plasticity, resistance to apoptosis, and modified responses to chemotherapy and immunotherapy. It also explores the interaction between BHB and the tumor microenvironment (TME), emphasizing how BHB can influence immune responses and tumor progression. Given the complexity of BHB’s role in CRC, the review underscores the necessity for personalized approaches that consider the tumor’s genetic and metabolic characteristics. Understanding the dual role of BHB in CRC is essential for devising more effective therapeutic strategies that can either harness or counteract its effects, thereby guiding the application of ketogenic diets and other metabolic interventions in the treatment of CRC.