β-Hydroxybutyrate promotes cancer metastasis through β-hydroxybutyrylation-dependent stabilization of Snail

作者：Wenna Jiang, Meng Wang, Jiayi Wang, Qianhui Hao, Yuxuan Li, Lin Liu, Tianxing Zhou, Wei Song, Jing Liu, Miao Liu, Yongjie Xie, Duo Zuo, Jiawei Xiao, Xiuse Zhang, Shan Gao, Li Ren, Jihui Hao · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61541-3 · 被引用次数：11 · 研究领域：Diet and metabolism studies、Cancer, Hypoxia, and Metabolism、Metabolomics and Mass Spectrometry Studies

β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completely unknown in cancer metastasis. Here, we report that β-hydroxybutyrate (BHB) is clinically associated with the progression of pancreatic cancer and functionally promotes pancreatic cancer cell metastasis. Mechanistically, BHB induces Kbhb modification of Snail at lysine 152 to enhance Snail stabilization, which is regulated by Kbhb modification enzyme CREB-binding protein (CBP), and subsequently prevents Snail degradation by blocking recognition of E3 ubiquitin ligases FBXL14. Furthermore, either targeting Snail Kbhb modification or CBP inhibitor decreases cancer metastasis and enhances the therapeutic efficacy of gemcitabine in pancreatic cancer cells. Collectively, our study reveals that Kbhb of Snail is critical to promote metastasis and provides a potential therapeutic strategy. Snail is involved in the regulation of epithelial-mesenchymal transition and metastasis. Here, the authors show that the metabolite β-hydroxybutyrate promotes pancreatic cancer metastasis through protecting Snail from degradation.