Artesunate Exploits Glutathione-Dependent Redox Vulnerability in Metastatic Lung Adenocarcinoma

Abstract

Metastatic dissemination remains the principal cause of mortality in lung adenocarcinoma. To identify metabolic vulnerabilities associated with metastasis, we used cell lines with distinct metastatic abilities derived from the KrasG12D;p53KO mouse model. Building on evidence of mitochondrial dysfunction in metastasis-derived cells, we performed an in vivo screen of a focused metabolic drug library using a multiplexed DNA-barcoding platform. This approach identified artesunate as a selective inhibitor of metastatic seeding, which was validated in vivo to reduce metastatic burden while leaving primary tumor growth unaffected. Mechanistically, artesunate induced oxidative stress, characterized by reactive oxygen species and lipid peroxidation. Transcriptomic and mechanistic profiling revealed altered redox homeostasis in metastasis-derived cells. Inhibition of glutathione synthesis specifically sensitized these cells to artesunate, resulting in extensive cell death, whereas primary tumor-derived cells remained resistant. These findings identify glutathione-dependent redox homeostasis as a metabolic vulnerability in metastatic cells that can be specifically targeted using artesunate.