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

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 () and Jihui Hao ()
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Wenna Jiang: Tianjin’s Clinical Research Center for Cancer
Meng Wang: Tianjin’s Clinical Research Center for Cancer
Jiayi Wang: Tianjin’s Clinical Research Center for Cancer
Qianhui Hao: Tianjin’s Clinical Research Center for Cancer
Yuxuan Li: Tianjin’s Clinical Research Center for Cancer
Lin Liu: Tianjin’s Clinical Research Center for Cancer
Tianxing Zhou: Tianjin’s Clinical Research Center for Cancer
Wei Song: Nanjing Agricultural University
Jing Liu: Shanghai Cancer Center
Miao Liu: Tianjin’s Clinical Research Center for Cancer
Yongjie Xie: Tianjin’s Clinical Research Center for Cancer
Duo Zuo: Tianjin’s Clinical Research Center for Cancer
Jiawei Xiao: Tianjin’s Clinical Research Center for Cancer
Xiuse Zhang: Tianjin’s Clinical Research Center for Cancer
Shan Gao: Southeast University
Li Ren: Tianjin’s Clinical Research Center for Cancer
Jihui Hao: Tianjin’s Clinical Research Center for Cancer

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61541-3

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