Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis

Thymosin beta 4 (T beta 4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. T beta 4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of T beta 4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of T beta 4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron(2+) and iron(3+) binding regions along the peptide and show that the presence of T beta 4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, T beta 4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that T beta 4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of T beta 4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled T beta 4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.

Automated summary

Thymosin beta 4 (T beta 4) is a protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. This study reveals the important role of T beta 4 in an iron-dependent form of cell death, and its potential therapeutic implications in cancer and neurodegenerative diseases.