The AMPK activator A769662 promotes ferroptosis and suppresses disulfidptosis by inhibiting SLC7A11.

AMP-activated protein kinase (AMPK) plays a critical role in maintaining cellular energy homeostasis. Activation of AMPK negatively regulates ferroptosis, a form of cell death caused by iron-dependent accumulation of lipid peroxides. In the present study, we unexpectedly found that A769662, widely used as a selective AMPK activator, inhibited SLC7A11-mediated cystine uptake, thereby decreasing intracellular reduced glutathione (GSH) levels and promoting ferroptosis in glioblastoma cells. Deletion of the AMPKα1 gene or treatment with an AMPK inhibitor compound C did not inhibit A769662-induced promotion of ferroptosis. In addition, A769662 suppressed disulfidptosis, a recently identified form of cell death caused by SLC7A11-mediated cystine uptake under glucose deprivation. On the other hand, AICAR, another AMPK activator, had no effect on cystine uptake and intracellular GSH levels. These results suggest that A769662 inhibits SLC7A11-mediated cystine uptake to promote ferroptosis and suppress disulfidptosis in an AMPK-independent manner.