J Nutr Biochem. 2026 Feb 11:110312. doi: 10.1016/j.jnutbio.2026.110312. Online ahead of print.

ABSTRACT

Breast cancer (BC) is one of the most prevalent malignant tumors among women globally. This disease is modulated by the interaction of multiple complex factors and exhibits a high mortality rate, posing a severe threat to women’s lives and health. The ketogenic diet (KD), a dietary regimen characterized by high fat and low carbohydrate content, has emerged as a potential adjuvant therapeutic strategy for BC; however, its mechanistic roles in regulating tumor metabolism remain not fully elucidated. In the present study, the underlying mechanism of KD in the context of BC were investigated in depth. In 4T1 mammary tumor-bearing mice, KD suppressed tumor growth by 50.73% (P<0.01) and activated the AMPK-mTOR axis, as evidenced by a 2.1-fold increase in AMPK phosphorylation and a reduction in mTOR activity. At the cellular level, Glucose restriction regulated mTOR expression at the cellular level by upregulating intracellular reactive oxygen species (ROS) in 4T1 cells and activating AMPK. Combining results at the animal and cellular levels, KD may induce alternations in intracellular ROS levels by restricting glucose uptake, thereby modulating the expression of the AMPK-mTOR pathway and ultimately inhibiting tumor growth. Collectively, our results demonstrate that KD exerts anti-tumor effects via ROS-mediated regulation of the AMPK/mTOR signaling pathway, supporting its potential as a metabolic intervention strategy for BC.

PMID:41688032 | DOI:10.1016/j.jnutbio.2026.110312

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