Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer

Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer

Cell Metabolism

10.1016/j.cmet.2025.10.001

https://doi.org/10.1016/j.cmet.2025.10.001

Zhengwei Wu, Zhenxun Wang, Seow Qi Ng, Jessica Alice Lidster, Paul Schwerd-Kleine, Zi Jin Cheryl Phua, Kai Lay Esther Peh, Yin Ying Ho, Ju Yuan, S. Shathishwaran, Xun Hui Yeo, Ying Zhang, Yui Hei Jasper Chiu, Li Yieng Eunice Lau, Tony Kiat Hon Lim, Angela Takano, Eng Huat Tan, Anders Jacobsen Skanderup, Vinay Tergaonkar, Weiping Han, Ying Swan Ho, Daniel Shao Weng Tan, Wai Leong Tam

Metabolic reprogramming, Ketone metabolism, Ketogenic diet, Tumor-initiating cells, MCT1 monocarboxylate transporter, CD147, Glucose stress, lung cancer cells

24 October 2025

Wu, Z., Wang, Z., Ng, S. Q., Lidster, J. A., Schwerd-Kleine, P., Phua, Z. J. C., Peh, K. L. E., Ho, Y. Y., Yuan, J., Shathishwaran, S., Yeo, X. H., Zhang, Y., Chiu, Y. H. J., Lau, L. Y. E., Lim, T. K. H., Takano, A., Tan, E. H., Skanderup, A. J., Tergaonkar, V., … Tam, W. L. (2025). Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer. Cell Metabolism, 37(11), 2233-2249.e9. https://doi.org/10.1016/j.cmet.2025.10.001

Tumor-initiating cells (TICs) tend to reside in poorly vascularized regions of tumors and are subjected to nutrient stress. How TICs activate metabolic plasticity for adapting to periods of low nutrient availability, especially during glucose-limiting conditions, has remained unclarified. Here, we discover that lung TICs can induce a metabolic switch from glucose towards ketone utilization specifically during glucose deprivation, whereas bulk, non-TIC cells are unable to do so. Through ex vivo supplementation of ketones or keeping mice on prolonged ketogenic diet, we determine the functional importance of ketones in maintaining the growth and tumor-initiating property of lung TICs. Metabolomics, genomics and metabolic flux tracing studies reveal that ketones feed into ketolysis, fatty acid synthesis and de novo lipogenesis pathways. Surprisingly, ketogenic diet programs the metabolic addiction of TICs towards ketolysis, and this paradoxically induces their therapeutic sensitivity towards the inhibition of the monocarboxylate transporter, MCT1, which imports ketones into cells. Additionally, pharmacological inhibition of fatty acid synthase (FASN) also exerts a more pronounced anti-tumorigenic response in the context of a ketogenic diet. MCT1 function is regulated by the chaperone protein, CD147, and its loss is sufficient to ablate lung TICs under glucose-limiting conditions in vitro and in vivo. Our data reveal a metabolic switch that lung TICs adopt to overcome nutrient stress, and provide the mechanistic bases for how diet manipulation can alter the course of cancer progression or enhance the efficacy of targeted therapy in a context-dependent manner.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Medical Research Council - Open Fund - Individual Research Grant
Grant Reference no. : OFIRG21nov-0068

This research / project is supported by the National Medical Research Council - Open Fund - Large Collaborative Grant
Grant Reference no. : NMRC/OFLCG/002-2018

This research / project is supported by the National Medical Research Council - Open Fund - Large Collaborative Grant
Grant Reference no. : MOH-OFLCG21jun-0001

This research / project is supported by the National Medical Research Council - Open Fund - Young Individual Research Grant
Grant Reference no. : OFYIRG22jul-0034

This research / project is supported by the National Medical Research Council - Open Fund - Large Collaborative Grant
Grant Reference no. : OFLCG24may-0028

This research / project is supported by the National Research Foundation - NRF Investigatorship
Grant Reference no. : NRF-NRFI08-2022

This research / project is supported by the National Research Foundation - The National Research Foundation Competitive Research Programme
Grant Reference no. : NRF-CRP22-2019-0003

This research / project is supported by the National Research Foundation - The National Research Foundation Competitive Research Programme
Grant Reference no. : NRF-CRP23-2019-0004

This research / project is supported by the Singapore Ministry of Education - Research Centres of Excellence initiative
Grant Reference no. : NA

https://oar.a-star.edu.sg/communities-collections/articles/22571

1550-4131

Genome Institute of Singapore

https://doi.org/10.1016/j.cmet.2025.10.001