While the ketogenic diet has emerged as a promising nutritional intervention in cancer therapy, the core signaling pathway through which ketone body signals are sensed remains elusive. Concurrently, the mTORC1 pathway is a well-established central hub for sensing nutrients and energy, and whether and how this pathway senses and responds to ketone body signals had not been clearly defined.
The study focuses on uncovering the potential connection mechanism between ketone bodies and the mTORC1 pathway to elucidate the deeper biological principles underlying the anti-cancer effects of a ketogenic diet.
Major Findings:
- β-hydroxybutyrate (BHB) specifically inhibits mTORC1 and CRC growth: Only D-BHB (not L-BHB or other ketones) potently suppresses mTORC1 activity and tumor/organoid growth in various models (cells, mouse/human organoids, mouse models). This effect is mediated through the mTORC1 pathway.
- BHB acts via RagC β-hydroxybutyrylation (Kbhb): Kbhb proteomic analysis identifies RagC as a key target, and mass spectrometry and mutagenesis pinpoint K349 as the critical site. The acetyltransferase p300 catalyzes RagC-K349bhb, while the deacetylase SIRT1 removes it.
- Molecular mechanism of inhibition: The K349bhb modification reduces RagC's GTP-bound state, disrupts its binding to Raptor/mTOR, and prevents mTORC1 lysosomal localization, leading to pathway inactivation.
- In vivo genetic validation: RagC-K348R knock-in mice completely lose the tumor-suppressive and mTORC1-inhibitory effects of BHB and KD, proving the necessity of this specific modification in vivo.
- Clinical correlation: In human CRC patient samples, tissue levels of BHB and RagC-K349bhb are negatively correlated with tumor size, mTORC1 activity (p-S6), and tumor markers (CA199, CEA).
This study identifies RagC as a novel BHB sensor, expanding the paradigm of mTORC1 nutrient sensing to include metabolite-driven covalent modifications (Kbhb) and highlights RagC-K349bhb as a potential therapeutic target for BHB-based CRC treatment strategies.
