Wang Dongxu, Yin Kai, Zhang Yue, Lu Hongmin, Hou Lulu, Zhao Hongjing, Xing Mingwei
College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China.
College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China.
Comp Biochem Physiol C Toxicol Pharmacol. 2023 Feb;264:109526. doi: 10.1016/j.cbpc.2022.109526. Epub 2022 Nov 29.
Fluoride (F) is an environmental pollutant that continues to threaten human health. Long-term or excessive fluoride exposure can cause a series of acute or chronic systemic and organ-specific diseases. The liver is considered to be one of the important target organs of fluoride poisoning, however, the specific cause of liver damage caused by fluoride is still unclear. In the present study, we identified ferroptosis as a key mechanism of fluoride-induced liver injury. Under fluorosis conditions, lipid peroxidation levels in the liver are significantly increased and iron overload is induced. Combined transcriptomic and metabolomic analysis revealed that activation of the SIRT1/FOXOs pathway is one of the main causes of fluorosis-induced liver damage. Further analysis by in vitro experiments showed that the SIRT1/FOXOs pathway can cause the activation of the Nrf2/HO-1 pathway under the condition of fluorosis, and can activate the P53-dependent ferroptosis pathway, leading to the occurrence of lipid peroxidation and iron accumulation, ultimately leading to ferroptosis. Our study provides insight into the mechanism of fluoride-induced liver injury, and our results also provide strategies for treatment to alleviate liver injury caused by fluorosis.
氟化物（F）是一种持续威胁人类健康的环境污染物。长期或过量接触氟化物会引发一系列急性或慢性全身性及器官特异性疾病。肝脏被认为是氟中毒的重要靶器官之一，然而，氟化物导致肝脏损伤的具体原因仍不明确。在本研究中，我们确定铁死亡是氟化物诱导肝损伤的关键机制。在氟中毒条件下，肝脏中的脂质过氧化水平显著升高，并诱导铁过载。转录组学和代谢组学联合分析表明，SIRT1/FOXOs通路的激活是氟中毒诱导肝损伤的主要原因之一。体外实验进一步分析表明，SIRT1/FOXOs通路在氟中毒条件下可导致Nrf2/HO-1通路激活，并可激活P53依赖的铁死亡通路，导致脂质过氧化和铁蓄积的发生，最终导致铁死亡。我们的研究深入了解了氟化物诱导肝损伤的机制，我们的结果也为缓解氟中毒所致肝损伤的治疗提供了策略。
