Ketogenesis promotes triple-negative breast cancer metastasis via calpastatin β-hydroxybutyrylation.

Triple-negative breast cancer (TNBC) continues to pose a significant obstacle in the field of oncology. Dysregulation of lipid metabolism, notably upregulated ketogenesis, has emerged as a hallmark of TNBC, yet its role in metastasis has been elusive. Here, by utilizing clinical specimens and experimental models, the study demonstrates that increased ketogenesis fosters TNBC metastasis by promoting the up-regulation of β-hydroxybutyrate (β-OHB), a key ketone body. Mechanistically, β-OHB facilitates β-hydroxybutyrylation (Kbhb) of Calpastatin (CAST), an endogenous calpain (CAPN) inhibitor, at K43, blocking the interaction with CAPN and subsequently promoting FAK phosphorylation and epithelial‒mesenchymal transition (EMT). In conclusion, the study reveals a novel regulatory axis linking ketogenesis to TNBC metastasis, shedding light on the intricate interplay between metabolic reprogramming and tumor progression.
Competing Interests: Declarations Ethical approval All experiments received approval from the Clinical Trial Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (KY2024-R080) and were conducted in accordance with the Helsinki Declaration principles. Animal experiments were conducted with the approval of the Animal Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University in accordance with the Regulations on the Management of Experimental Animals. Competing interests The authors declare no competing interests.
(© 2024. The Author(s).)