Lachowicz Joanna I, Pichiri Giusi, Piludu Marco, Fais Sara, Orrù Germano, Congiu Terenzio, Piras Monica, Faa Gavino, Fanni Daniela, Dalla Torre Gabriele, Lopez Xabier, Chandra Kousik, Szczepski Kacper, Jaremko Lukasz, Ghosh Mitra, Emwas Abdul-Hamid, Castagnola Massimo, Jaremko Mariusz, Hannappel Ewald, Coni Pierpaolo
Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy.
Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy.
Int J Mol Sci. 2022 Jan 4;23(1):551. doi: 10.3390/ijms23010551.
Thymosin β4 (Tβ4) 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. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 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 Tβ4 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 and iron binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tβ4 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 Tβ4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tβ4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.
胸腺素β4（Tβ4）于40年前从小牛胸腺中提取。从那时起，它就被确定为一种与凝血、组织再生、血管生成和抗炎过程有关的G-肌动蛋白结合蛋白。Tβ4也与肿瘤转移和神经退行性变有关。然而，Tβ4在这些过程中的确切作用和作用机制在很大程度上仍然未知，G-肌动蛋白的结合不足以解释这些多种作用。在这里，我们首次确定了Tβ4机制在铁死亡（一种铁依赖性细胞死亡形式）中的重要作用，铁死亡会导致神经退行性变，并在某种程度上保护癌细胞免于细胞死亡。具体而言，我们展示了该肽段上的四个铁及铁结合区域，并表明细胞生长培养基中Tβ4的存在可抑制巨噬细胞系中erastin和谷氨酸诱导的铁死亡。此外，Tβ4可增加氧化应激相关基因的表达，即BAX、血红素加氧酶-1、热休克蛋白70和硫氧还蛋白还原酶1，这些基因在铁死亡过程中表达下调。我们提出假说，Tβ4是一种内源性铁螯合剂，并参与铁死亡过程中的铁稳态。我们讨论了Tβ4和铁死亡同时参与不同人类疾病（主要是癌症和神经退行性变）的文献数据。我们的研究结果与文献数据对比表明，控制Tβ4的释放可以控制铁死亡的开启/关闭转换，并可能为癌症和组织退行性疾病提供新的治疗机会。
