Department of Clinical Pharmacy, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China.
Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
J Pharmacol Sci. 2021 Feb;145(2):175-186. doi: 10.1016/j.jphs.2020.11.012. Epub 2020 Nov 26.
Bavachin (BV), a natural flavonoid compound derived from Psoralea corylifolia L, has been reported to be a potential hepatotoxin. Our previous studies have found that BV can induce endoplasmic reticulum (ER) stress-related cell apoptosis, but the molecular mechanism underlying BV-induced ER stress remains obscure. Sestrin2, a highly conserved stress-inducible protein, is involved in the cellular responses of various stress conditions and homeostatic regulation. However, whether Sestrin2 participated in the ER stress related hepatotoxicity against BV is still elusive. In the present study, we aim to investigate the role of BV on liver injury of mice and the impact of Sestrin2 on BV-induced ER stress in HepG2 cells. The results in mice showed that BV induced ER stress related liver injury with increased Sestrin2 expression involvement. Knockdown of Sestrin2 with siRNA aggravated BV-induced ER stress significantly in HepG2 cells. Further mechanistic study uncovered that inhibition of mTORC1 with rapamycin blocked BV-induced ER stress, and treatment with Sestrin2 siRNA blocked the inhibition effect of AMPK to mTORC1. Therefore, constant mTORC1 would lead to accumulation of misfolded or unfolded proteins and aggravated ER stress. Collectively, our study indicates that Sestrin2 confers protection against BV-induced ER stress via activating of the AMPK/mTORC1 pathway.
补骨脂素（BV），一种从 Psoralea corylifolia L 中提取的天然类黄酮化合物，已被报道为一种潜在的肝毒素。我们之前的研究发现，BV 可以诱导内质网（ER）应激相关的细胞凋亡，但 BV 诱导 ER 应激的分子机制尚不清楚。Sestrin2 是一种高度保守的应激诱导蛋白，参与多种应激条件和体内平衡调节的细胞反应。然而，Sestrin2 是否参与了 BV 诱导的 ER 应激相关肝毒性仍不清楚。在本研究中，我们旨在研究 BV 对小鼠肝脏损伤的作用以及 Sestrin2 对 HepG2 细胞中 BV 诱导的 ER 应激的影响。在小鼠中的结果表明，BV 诱导 ER 应激相关的肝损伤，伴随着 Sestrin2 表达的增加。用 siRNA 敲低 Sestrin2 显著加重了 HepG2 细胞中 BV 诱导的 ER 应激。进一步的机制研究表明，用雷帕霉素抑制 mTORC1 阻断了 BV 诱导的 ER 应激，而用 Sestrin2 siRNA 阻断了 AMPK 对 mTORC1 的抑制作用。因此，持续的 mTORC1 会导致错误折叠或未折叠的蛋白质积累，加重 ER 应激。综上所述，我们的研究表明，Sestrin2 通过激活 AMPK/mTORC1 通路对 BV 诱导的 ER 应激提供保护。
