SMG9 drives ferroptosis by directly inhibiting GPX4 degradation.

Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that plays an integral role in eliminating abnormal mRNA and corresponding proteins. It is unclear whether the NMD pathway is involved in regulating ferroptosis, which is a type of iron-dependent cell death mainly caused by the inhibition of the antioxidant SLC7A11-GPX4 axis. In this study, we conducted a small-scale RNAi screen and proved that SMG9, a component of the NMD machinery, is a selective driver for ferroptosis in human cancer cells. SMG9 positively regulates ferroptosis independent of its activity in NMD. Instead, SMG9 is a direct binding protein of GPX4 to promote the degradation of GPX4 in response to RSL3 (a GPX4 inhibitor), but not erastin (a SLC7A11 inhibitor). The genetic inhibition of SMG9 increases the accumulation of GPX4 in the mitochondria, thereby preventing mitochondrial oxidative damage, and ultimately favoring ferroptosis resistance in vitro or in xenograft mouse models. Overall, these findings establish a new mitochondrial regulation mechanism that can affect ferroptosis-mediated tumor suppression.