Related Experiment Video
Updated: Nov 1, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
SMG9 drives ferroptosis by directly inhibiting GPX4 degradation
Leng Han1, Lulu Bai2, Xue Fang1
1Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China.
Abstract:
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.
Insights
SMG9 drives ferroptosis in cancer cells by degrading GPX4, independent of its role in nonsense-mediated mRNA decay. Inhibiting SMG9 enhances GPX4, conferring resistance to ferroptosis and promoting tumor suppression.
Area of Science:
- Cellular biology
- Molecular mechanisms of cell death
- Cancer research
Background:
- Nonsense-mediated mRNA decay (NMD) is a crucial cellular quality control pathway.
- Ferroptosis, an iron-dependent cell death, is regulated by the SLC7A11-GPX4 axis.
- The role of NMD in ferroptosis regulation remains largely unknown.
Purpose of the Study:
- To investigate the involvement of the NMD pathway in ferroptosis regulation.
- To identify specific NMD components that influence ferroptosis in cancer cells.
- To elucidate the molecular mechanism by which SMG9 regulates ferroptosis.
Main Methods:
- Small-scale RNAi screening in human cancer cells.
- Investigating the interaction between SMG9 and GPX4.
- Assessing the impact of SMG9 inhibition on GPX4 levels and ferroptosis.
- Utilizing in vitro and xenograft mouse models.
Main Results:
- SMG9, an NMD component, selectively drives ferroptosis in cancer cells.
- SMG9 promotes GPX4 degradation independently of its NMD function.
- SMG9 directly binds GPX4, enhancing its degradation in response to RSL3.
- Genetic inhibition of SMG9 leads to GPX4 accumulation, mitochondrial protection, and ferroptosis resistance.
Conclusions:
- SMG9 acts as a novel regulator of ferroptosis through direct interaction with GPX4.
- This interaction is independent of SMG9's canonical NMD activity.
- SMG9 inhibition confers resistance to ferroptosis by stabilizing GPX4 and protecting mitochondria.
- Findings reveal a new mitochondrial regulation mechanism impacting ferroptosis-mediated tumor suppression.
More Related Videos
11:10Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
09:10Direct Gene Knock-out of Axolotl Spinal Cord Neural Stem Cells via Electroporation of CAS9 Protein-gRNA Complexes
Published on: July 9, 2019
