GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) is notorious for its poor prognosis. In the present study, the role of glutaminase 2 (GLS2) and copper (Cu) in the radiosensitivity of ESCC was explored. Both in vitro and in vivo experiments were conducted, and the results demonstrated that the knockdown of GLS2 could suppress cell proliferation and augment the sensitivity to radiotherapy (RT). The addition of Cu influenced cell viability and radiosensitivity. Notably, under normal GLS2 expression status, exogenous Cu augmented RT sensitivity without triggering cuproptosis. Mechanistically, the suppression of GLS2 interacted with Cu to downregulate lipoic acid synthase and dihydrolipoamide S-succinyltransferase, resulting in the reduction of the activity of α-ketoglutarate dehydrogenase complex and the obstruction of the tricarboxylic acid cycle, ultimately leading to the enhancement of RT sensitivity. These findings emphasize the significance of cuproptosis in ESCC radiotherapy and provide potential directions for therapeutic strategies.