TGF-β Suppresses Glycolytic Enzyme PFKM, Fueling Metabolic Shift and EMT in Lung Cancer

Lung adenocarcinoma remains one of the most prevalent and lethal malignancies worldwide, and a new study points to an unexpected metabolic switch that helps drive its progression. Researchers report that transforming growth factor-β (TGF-β), a predominant driver of epithelial-mesenchymal transition (EMT), markedly downregulates phosphofructokinase-M (PFKM), the rate-limiting enzyme of glycolysis. The work, published as an open-access original article in Cellular and Molecular Life Sciences, links this enzymatic suppression to both altered glucose handling and invasive cellular behavior.

According to the study, PFKM suppression acts as a critical metabolic switch in lung adenocarcinoma cells. Rather than accelerating glycolysis, the loss of PFKM shunts glucose carbon flux toward glycogen accumulation, a reprogramming that promotes cell survival under glucose deprivation. The authors describe this as an alternative glucose metabolic program distinct from the conventional glycolytic enhancement often associated with cancer metabolism.

The findings also connect metabolism directly to EMT. The researchers show that PFKM knockdown alone is sufficient to induce a mesenchymal-like state, significantly enhancing cellular migration and invasion. This positions PFKM downregulation as a pivotal node integrating metabolic reprogramming with EMT, two processes that are well-established drivers of tumor progression and metastasis but whose coupling mechanisms have remained elusive.

By identifying this mechanistic link, the study addresses a gap that has hindered the development of targeted therapeutic strategies. The authors conclude that these insights identify PFKM as a promising therapeutic target in lung adenocarcinoma. As an early-release, peer-reviewed accepted article carrying a permanent DOI, the version is subject to further edits before the final Version of Record appears.

Subject of Research: How TGF-β-induced PFKM downregulation couples metabolic reprogramming to EMT in lung adenocarcinoma

Article Title: TGF-β-induced PFKM downregulation drives metabolic reprogramming, EMT, and malignant progression in lung adenocarcinoma

Article References: Zhang, B., Chen, Y., Zhang, X., Sun, C., Wang, X., Li, H., Silva, J. C. R., & Thiery, J. P. (2026). TGF-β-induced PFKM downregulation drives metabolic reprogramming, EMT, and malignant progression in lung adenocarcinoma. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06494-6

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06494-6

Keywords: lung adenocarcinoma, TGF-β, PFKM, glycolysis, metabolic reprogramming, EMT, glycogen accumulation, glucose deprivation, cell migration, invasion, therapeutic target, cancer metabolism