PDF(Pubmed)
Abstract：
Ferroptosis hallmarked by lipid peroxidation and iron homeostasis imbalance is involved in the occurrence and development of various diseases. The plant growth regulator chlormequat chloride (CCC) can contribute to the causality and exacerbation of reproductive disorders. However, the mechanism by which CCC may cause Leydig cell attenuation remains poorly understood. In this study, TM3 Leydig cells were used to investigate the inhibitory effect of CCC on cell growth and its possible mechanism. The results showed that CCC caused apoptosis, pyroptosis, ferroptosis and necroinflammation in TM3 cells. By comparing the effects of ferroptosis inhibitor Ferrostatin-1 (Fer-1) and pan-Caspase inhibitor Z-VAD-FMK (ZVF) on lipid peroxidation and Caspase-mediated regulated cell death (RCD), we found that Fer-1 was better at rescuing the growth of TM3 cells than ZVF. Although ZVF reduced mitochondrial ROS level and inhibited the activation of Caspase3 and Caspase1, it could not significantly ameliorate lipid peroxidation and the levels of IL-1β and HMGB1 like Fer-1. Therefore, ferroptosis might be a key non apoptotic RCD mode responsible for CCC-driven inflammation, leading to weakened viability and proliferation of TM3 cells. In addition, overexpression of ferritin light chain (FTL) promoted the resistance of TM3 cells to CCC-induced ferroptosis-mediated inflammation and to some extent improved the inhibition of viability and proliferation. Altogether, ferroptosis-initiated inflammation might play a key role in CCC-impaired TM3 cell growth.
摘要：
以脂质过氧化和铁稳态失衡为特征的铁凋亡参与了各种疾病的发生和发展。植物生长调节剂氯化氯mequat（CCC）可导致生殖障碍的因果关系和恶化。然而,CCC可能导致Leydig细胞衰减的机制尚不清楚。在这项研究中,用TM3Leydig细胞研究CCC对细胞生长的抑制作用及其可能机制。结果表明，CCC引起细胞凋亡，焦亡,TM3细胞的铁凋亡和坏死性炎症。通过比较铁凋亡抑制剂Ferrostatin-1（Fer-1）和pan-Caspase抑制剂Z-VAD-FMK（ZVF）对脂质过氧化和Caspase介导的调节性细胞死亡（RCD）的影响，我们发现Fer-1比ZVF更能挽救TM3细胞的生长。尽管ZVF降低了线粒体ROS水平并抑制了Caspase3和Caspase1的活化，但它不能像Fer-1一样显着改善脂质过氧化和IL-1β和HMGB1的水平。因此,铁凋亡可能是负责CCC驱动的炎症的关键非凋亡RCD模式，导致TM3细胞活力和增殖减弱。此外,铁蛋白轻链（FTL）的过表达促进了TM3细胞对CCC诱导的铁凋亡介导的炎症的抗性，并在一定程度上改善了对活力和增殖的抑制作用。总之,铁凋亡引发的炎症可能在CCC受损的TM3细胞生长中起关键作用。
