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Updated: May 10, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation
Peixiang Zheng1,2, Zhiqiang Hu1,2, Yuli Shen1,2
1Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Tumor cells adapt to the inflammatory tumor microenvironment (TME) and develop resistance to immunotherapy, with ferroptosis being a major form of tumor cell death. However, the mechanisms by which tumor cells coordinate TME stimuli and their unique metabolic traits to evade ferroptosis and develop resistance to immunotherapy remain unclear. Here we showed that interferon-γ (IFNγ)-activated calcium/calmodulin-dependent protein kinase II phosphorylates phosphoserine aminotransferase 1 (PSAT1) at serine 337 (S337), allowing it to interact with glutathione peroxidase 4 (GPX4) and stabilize the protein, counteracting ferroptosis. PSAT1 elevates GPX4 stability by promoting α-ketoglutarate-dependent PHD3-mediated GPX4 proline 159 (P159) hydroxylation, disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation. In mice, reconstitution of PSAT1 S337A or GPX4 P159A promotes ferroptosis and suppresses triple-negative breast cancer (TNBC) progression. Blocking PSAT1 pS337 with CPP elevates IFNγ-induced ferroptosis and enhances the efficacy of programmed cell death protein 1 (PD-1) antibodies in TNBC. Additionally, PSAT1-mediated GPX4 hydroxylation correlates with poor immunotherapy outcomes in patients with TNBC, highlighting PSAT1's noncanonical role in suppressing ferroptosis and immunotherapy sensitivity.
Insights
Tumor cells evade ferroptosis and immunotherapy resistance by stabilizing glutathione peroxidase 4 (GPX4) via phosphoserine aminotransferase 1 (PSAT1). Targeting this interaction suppresses triple-negative breast cancer (TNBC) and enhances immunotherapy efficacy.
Area of Science:
- Cancer Biology
- Immunology
- Cellular Metabolism
Background:
- Tumor cells resist immunotherapy by adapting to the tumor microenvironment (TME) and evading ferroptosis.
- Mechanisms linking TME stimuli, metabolic traits, ferroptosis evasion, and immunotherapy resistance are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which tumor cells evade ferroptosis and develop resistance to immunotherapy.
- To identify novel therapeutic targets for enhancing immunotherapy efficacy in triple-negative breast cancer (TNBC).
Main Methods:
- Investigated the role of interferon-γ (IFNγ) signaling in regulating ferroptosis.
- Utilized biochemical assays and mouse models to study protein-protein interactions and phosphorylation events.
- Assessed the impact of targeting PSAT1 and GPX4 on ferroptosis induction and tumor progression in TNBC.
Main Results:
- IFNγ-activated calcium/calmodulin-dependent protein kinase II phosphorylates PSAT1, which stabilizes GPX4 and inhibits ferroptosis.
- PSAT1 stabilizes GPX4 through PHD3-mediated hydroxylation, preventing its degradation.
- Targeting PSAT1 phosphorylation or GPX4 hydroxylation promoted ferroptosis, suppressed TNBC progression in mice, and enhanced anti-PD-1 therapy efficacy.
- PSAT1-mediated GPX4 hydroxylation correlated with poor immunotherapy outcomes in TNBC patients.
Conclusions:
- PSAT1 plays a noncanonical role in suppressing ferroptosis by stabilizing GPX4.
- Targeting the PSAT1-GPX4 axis represents a promising strategy to overcome immunotherapy resistance in TNBC.
- PSAT1-mediated GPX4 hydroxylation serves as a potential biomarker for predicting immunotherapy response in TNBC.
