In a study entitled "Tumor suppressor Par-4 activates autophagy-dependent ferroptosis" published in the international journal Communications Biology on June 17, 2024, Research by scientists at NYU ABU Dhabi and other institutions has shown that Prostate apoptosis response 4 (Par-4) can cause a specific type of cell death called iron death in glioblastoma without damaging healthy cells, This new understanding could help scientists develop new therapies to treat refractory cancers and neurodegenerative diseases.

Iron death also plays an important role in a variety of health problems in the body, such as cancer, heart disease, brain damage, kidney failure, lung damage and diseases such as Parkinson's disease, Huntington's disease and Alzheimer's disease, and ferroptosis is a unique form of iron-dependent non-apoptotic cell death. Its main characteristic is the occurrence of destructive lipid peroxidation. Iron death is caused by the production of reactive oxygen species (ROS) mediated by iron ions and the subsequent lipid peroxidation process, which plays an important role in atrophy of cancerous tumors. In this study, for the first time, the researchers found that Par-4 was shown to promote iron death in glioblastoma cells.

Through unbiased RNA sequencing, the researchers demonstrated that multiple tumor suppressor proteins Par-4/PAWR are activated during iron death. Functional studies have shown that gene depletion of Par-4 effectively prevents iron death, while overexpression of Par-4 makes cells sensitive to iron death. What's more, Par-4 induced iron death is mechanistically driven by autophagy. Upregulation of Par-4 promotes activation of ferritin autophagy (autophagic degradation of ferritin) through nuclear receptor coactivator 4 (NCOA4), leading to excessive release of free unstable iron, which enhances lipid peroxidation and iron death. Inhibition of Par-4 significantly inhibited the NCOA4-mediated ferritin autophagy signaling axis. The results also showed that Par-4 activation was positively correlated with reactive oxygen species (ROS) production, which is critical for ferritin autophagy mediated iron death. In addition, knockdown of Par-4 effectively blocked iron death-mediated tumor inhibition in mouse xenotransplantation models. Together, these findings suggest that Par-4 plays a crucial role in iron death and could be further used in cancer treatment.

In summary, the results of this study indicate that the special protein Par-4 plays an important role in the occurrence of iron death, and Par-4 induced iron death is an important breakthrough in the development of cancer therapies. Developing ways to activate alternative cell death pathways may provide researchers with the opportunity to develop more effective therapies to help treat human glioblastoma and other deadly diseases.

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