Chemotherapy is a standard method in traditional treatment for gastric cancer. It is well known that the anti-tumor effects of chemotherapy are achieved mainly through the direct killing of cancer cells via apoptosis. However, chemotherapy often fails due to drug resistance. Therefore, non-apoptotic cell death induction by ferroptosis has recently been proposed as a new therapeutic modality to ablate cancer. In this study, we determined the role of MKL-1 in ferroptosis. In vitro and in vivo experiments showed that inhibition of MKL-1 expression significantly enhanced cell sensitivity to ferroptosis-inducing agents. It functions by targeting system Xc- to affect the synthesis of GSH in cells. Therefore, we developed an exosome-based therapeutic approach targeting MKL-1, which provides a novel insight into the treatment of gastric cancer.© The author(s).