Work

Transcriptional activation of PHKG2 by TP53 promotes ferroptosis through nuclear export of NRF2 in head and neck squamous cell carcinoma

Year: 2025

Type: article

Abstract: Ferroptosis has emerged as a promising therapeutic target in cancer treatment, yet its regulatory mechanisms in head and neck squamous cell carcinoma (HNSCC) remain poorly understood. This study investigates the role of phosphorylase kinase gamma 2 (PHKG2) in regulating ferroptosis through the TP53/NRF2/GPX4 axis in HNSCC. Using bioinformatics analysis and clinical data evaluation, we identified PHKG2 as a ferroptosis driver gene and a favorable prognostic marker in HNSCC patients. PHKG2 expression was found to negatively correlate with the redox regulator NRF2 and the ferroptosis marker GPX4, suggesting a role in modulating oxidative stress. Mechanistic investigations revealed that TP53 activation induces PHKG2 expression, which subsequently activates protein phosphatase 1 (PP1), leading to the nuclear export of NRF2. This cascade results in the downregulation of GPX4, depletion of intracellular reduced glutathione (GSH), and increased levels of reactive oxygen species (ROS), ultimately promoting ferroptosis characterized by mitochondrial damage. These findings indicate that the TP53/PHKG2 axis plays a critical role in ferroptosis regulation by disrupting redox homeostasis in HNSCC. Overall, this study highlights the potential of targeting the TP53-PHKG2-NRF2/GPX4 pathway as a therapeutic strategy to enhance ferroptosis and improve treatment efficacy in HNSCC. Our insights provide a strong foundation for developing novel approaches aimed at sensitizing HNSCC to ferroptosis-inducing agents, offering new opportunities for effective cancer treatment.

Source: Cell Death and Disease

DOI: 10.1038/s41419-025-07985-3