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

Lung adenocarcinoma (LUAD) remains one of the most prevalent and lethal malignancies worldwide. Although epithelial-mesenchymal transition (EMT) and glucose metabolic reprogramming are well-established drivers of tumor progression and metastasis, the mechanisms coupling these two processes remain elusive, hindering the development of targeted therapeutic strategies. This study shows that Transforming growth factor-β (TGF-β), a predominant driver of EMT, markedly downregulates the rate-limiting glycolytic enzyme phosphofructokinase-M (PFKM). PFKM suppression acts as a critical metabolic switch in LUAD, shunting glucose carbon flux toward glycogen accumulation and promoting cell survival under glucose deprivation. Notably, PFKM knockdown is sufficient to induce a mesenchymal-like state, significantly enhancing cellular migration and invasion. These findings establish PFKM downregulation as a pivotal node integrating metabolic reprogramming with EMT, revealing an alternative glucose metabolic program distinct from conventional glycolytic enhancement. Collectively, these insights identify PFKM as a promising therapeutic target in LUAD.