In a recent article published in Nature, Dmitrieva-Posocco et al.1 showed that ketogenic diets (KD) exert strong abilities to prevent and treat colorectal cancer (CRC) via the ketone body β-hydroxybutyrate (BHB)-mediated hydroxyl-carboxylic receptor.2 (Hcar2)-homeobox only protein homeobox (Hopx) signaling axis in multiple in vivo and in vitro models (Fig. 1). Intervention of this signaling axis through different settings can restrict the growth of CRC, which provides us a new insight for ketogenic diet-based CRC treatment.
Schematic illustration of the molecular mechanisms underlying KD-mediated suppression in CRC growth. During a ketogenic diet, abundant ketone bodies, especially BHB, were produced in the liver and were transferred to colorectum via blood circulation. Once the concentration of BHB elevated around colorectal tumor cells, it binds to Hcar2, a G-protein-coupled receptors, and activation Hopx expression, thereby inhibiting cell proliferation and tumorigenesis through suppressing proliferative pathway, such as cell cycle. In addition, multiple combination treatment based on KD demonstrated additive effects on the suppression of CRC, such as the combination with glucose restriction, histone deacetylases inhibitors, and DNA methylation inhibitor. BHB: β-hydroxybutyrate; Hcar2: hydroxyl-carboxylic receptor 2; α, β, γ: G-protein subunits; Hopx: homeobox only protein homeobox; HDAC: histone deacetylases
CRC is one of the most common malignant tumors in the world that threaten human health. Multiple meta-analyses have shown that a posteriori–derived unhealthy dietary pattern associated with higher body mass index and energy intake increased the risk of colon cancer,2 such as starchy foods, sugary drinks, salty snacks, red and processed meat, and refined carbohydrates. As Hippocrates said, ‘Let food be thy medicine and medicine be thy food’. Changing dietary pattern at different periods of treatment could indeed improve the therapeutic effect, such as fasting3 and high-fat diet.4 Even so, diet-based strategies for CRC prevention and therapy remain largely unclear. In this study, Dmitrieva-Posocco et al. detected the…