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Updated: Aug 5, 2026
Revealing the Ferroptotic Phenotype of Medulloblastoma
Published on: March 15, 2024
PET117 Deficiency Confers Ferroptosis Resistance Through ACSF2 Downregulation in Cervical Cancer
Qiong Sun1, Dandan Wang2, Qing Zhao3
1Shaanxi Belt and Road Joint Laboratory on Gut Microbiome and Cancer, Yulin Hospital, First Affiliated Hospital of Xi'an Jiao Tong University, Yulin 719000, China.
Abstract:
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic strategy for cervical cancer. However, the mitochondrial factors governing ferroptosis sensitivity in this malignancy remain incompletely understood. PET117, a conserved mitochondrial protein, has been implicated in mitochondrial homeostasis, yet its role in ferroptosis regulation and cervical cancer pathophysiology is unknown. Here, we report a novel role of PET117 in regulating ferroptosis. PET117 expression was significantly elevated in cervical cancer tissues and loss of PET117 in HeLa cells markedly suppressed erastin- and RSL3-induced ferroptosis. Mechanistically, PET117 deficiency attenuated intracellular reactive oxygen species (ROS) accumulation, lipid peroxidation, and iron overload. Mitochondrial proteomics and RNA-seq revealed extensive remodeling of the mitochondrial proteome and ferroptosis-related transcriptional networks upon PET117 depletion. Notably, integrative analysis of mitochondrial and nascent proteomes identified acyl-CoA synthetase family member 2 (ACSF2) as a downstream target of PET117. These findings establish PET117 as a novel regulator of ferroptosis in cervical cancer, thereby linking mitochondrial function to ferroptosis regulation.
Insights
PET117, a mitochondrial protein, is elevated in cervical cancer and promotes ferroptosis, a cell death pathway. Inhibiting PET117 reduces ferroptosis by decreasing reactive oxygen species and lipid peroxidation, offering a new therapeutic target.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Ferroptosis, an iron-dependent cell death, is a potential cervical cancer therapy.
- Mitochondrial regulation of ferroptosis in cervical cancer is not well understood.
- PET117's role in mitochondrial homeostasis is known, but its function in ferroptosis and cervical cancer is unclear.
Purpose of the Study:
- To investigate the role of PET117 in ferroptosis regulation.
- To explore PET117's involvement in cervical cancer pathophysiology.
- To identify downstream targets of PET117 in ferroptosis.
Main Methods:
- Quantified PET117 expression in cervical cancer tissues.
- Utilized CRISPR/Cas9 to deplete PET117 in HeLa cells.
- Assessed ferroptosis induction using erastin and RSL3.
- Measured intracellular reactive oxygen species (ROS), lipid peroxidation, and iron levels.
- Performed mitochondrial proteomics and RNA-sequencing.
- Integrated proteomic and transcriptomic data to identify downstream targets.
Main Results:
- PET117 expression is significantly increased in cervical cancer tissues.
- PET117 depletion suppressed erastin- and RSL3-induced ferroptosis in HeLa cells.
- PET117 deficiency reduced intracellular ROS, lipid peroxidation, and iron overload.
- Mitochondrial proteomics and RNA-seq showed significant remodeling upon PET117 depletion.
- ACSF2 was identified as a downstream target of PET117.
Conclusions:
- PET117 is a novel regulator of ferroptosis in cervical cancer.
- PET117 links mitochondrial function to ferroptosis sensitivity.
- Targeting PET117 may represent a therapeutic strategy for cervical cancer.
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