A preserved TGFβ cytostatic response through DLD-mediated metabolic modulation undermines anti-TGFβ therapy in gastric cancer.

ABSTRACT: Despite the well-known role of the transforming growth factor-β (TGFβ) pathway in cancer progression, therapies targeting it have largely failed in the clinic. This suggests our understanding of TGFβ's function is incomplete. Here we show that this therapeutic failure is rooted in a fundamental paradox: while TGFβ promotes malignant traits in gastric cancer, many cancer cells remain sensitive to its potent tumor-suppressive effects. We uncover that this suppression works by impairing the cell's energy metabolism through modulating dihydrolipoamide dehydrogenase (DLD). Therefore, broadly blocking the TGFβ pathway can inadvertently release a natural brake on tumor growth. Based on this insight, we demonstrate that co-targeting this metabolic vulnerability with an inhibitor (devimistat) along

SUBMITTER: Pan YQ 

PROVIDER: S-EPMC12618484 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature