Targeting Nrf2/PHKG2 axis to enhance radiosensitivity in NSCLC

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Ferroptosis is a promising anti-cancer strategy, but its mechanisms in non-small cell lung cancer (NSCLC) are not fully understood.
• Radiotherapy resistance is a significant challenge in NSCLC treatment.
• Identifying novel molecular targets is crucial for improving NSCLC therapeutic outcomes.

Purpose of the Study:

• To elucidate the regulatory mechanism of radiotherapy-induced ferroptosis in NSCLC via the NRF2/PHKG2 axis.
• To investigate the role of PHKG2 in NSCLC radiosensitivity and radioresistance.
• To develop a prognostic model for NSCLC patients based on ferroptosis-associated genes.

Main Methods:

• High-throughput transcriptome sequencing and Lasso risk regression analysis to identify ferroptosis-associated genes.
• Analysis of clinical NSCLC samples to assess PHKG2 expression changes post-radiotherapy.
• In vitro and in vivo experiments in NSCLC cells and tumor models to evaluate the NRF2/PHKG2 axis function.

Main Results:

• A Lasso risk regression model incorporating ferroptosis-associated genes accurately predicted NSCLC patient prognosis.
• Increased PHKG2 expression was observed in radiotherapy-sensitive NSCLC tissues.
• Overexpression of PHKG2 enhanced radiotherapy-induced ferroptosis by increasing intracellular iron and mitochondrial stress, while NRF2 was found to transcriptionally inhibit PHKG2.

Conclusions:

• The NRF2/PHKG2 axis plays a critical role in regulating ferroptosis and radiosensitivity in NSCLC.
• Targeting NRF2 to upregulate PHKG2 shows potential for overcoming radiotherapy resistance in NSCLC by promoting ferroptosis.
• The developed FAGs-Lasso risk regression model offers a valuable tool for NSCLC patient prognosis.