RagC senses β-hydroxybutyrate abundancy to suppress mTORC1

作者：GuoYan Wang, Qihang Hou, Yu Zhang, Qiuhui Duan, Jianxuan Gao, Jia‐Yi Wang, Jinrui Qiao, Yining Zheng, Xinjian Lei, Guowen Liu, Lin Lei, Tong Meng, Xiaojun Yang, Junhu Yao, Yu Li, Lu Deng · 发表于：Protein & Cell · 年份：2026 · DOI：10.1093/procel/pwag017 · 被引用次数：4 · 研究领域：Diet and metabolism studies、Cancer, Hypoxia, and Metabolism、Dietary Effects on Health

The ketogenic diet (KD), an emerging nutritional intervention for cancer, reprograms cellular energy metabolism from glucose to ketone bodies, including acetoacetate (AcAc), acetone (Ac), and β-hydroxybutyrate (BHB). However, the mechanisms connecting ketone body signal sensing to tumor growth suppression remain elusive. Here, we show that RagC, a key component of mTORC1 pathway, senses BHB but not AcAc and Ac, to dictate tumor suppression. KD-derived BHB inhibits mTORC1 activity by promoting β-hydroxybutyrylation (Kbhb) of RagC at lysine 349 (K348 in mice). Mechanistically, RagC-K349bhb is dynamically catalyzed by p300 and erased by SIRT1, disrupting RagC interaction with Raptor/mTOR and blocking mTORC1 recruitment to lysosomes. Clinically, BHB-mediated RagC-K349bhb suppresses colorectal cancer (CRC) growth via mTORC1 inhibition in both RagC-K348R knockin mice and CRC patient-derived samples. Thus, we identify a BHB sensing mechanism by mTORC1 and highlight the potential role of RagC-K349bhb as a therapeutic target for BHB-based CRC treatment.