Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China.
Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, China.
Cells. 2024 Jun 5;13(11):979. doi: 10.3390/cells13110979.
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.
铁死亡以脂质过氧化和铁平衡失调为特征，参与多种疾病的发生和发展。植物生长调节剂矮壮素（CCC）可导致生殖障碍的因果关系和恶化。然而，CCC 引起间质细胞瘤衰减的机制仍知之甚少。在这项研究中，TM3 间质细胞瘤用于研究 CCC 对细胞生长的抑制作用及其可能的机制。结果表明，CCC 导致 TM3 细胞凋亡、焦亡、铁死亡和坏死性炎症。通过比较铁死亡抑制剂 Ferrostatin-1（Fer-1）和全 Caspase 抑制剂 Z-VAD-FMK（ZVF）对脂质过氧化和 Caspase 调节的细胞死亡（RCD）的影响，我们发现 Fer-1 比 ZVF 更能挽救 TM3 细胞的生长。虽然 ZVF 降低了线粒体 ROS 水平并抑制了 Caspase3 和 Caspase1 的激活，但它不能像 Fer-1 那样显著改善脂质过氧化和 IL-1β 和 HMGB1 的水平。因此，铁死亡可能是一种关键的非凋亡 RCD 模式，负责 CCC 驱动的炎症，导致 TM3 细胞活力和增殖减弱。此外，转铁蛋白轻链（FTL）的过表达促进了 TM3 细胞对 CCC 诱导的铁死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。总之，铁死亡引发的炎症可能在 CCC 损害 TM3 细胞生长中起关键作用。
