Zhang Yuandie, Chen Hong, Chen Qianfeng, Zaitoun Margaret, Cheng Ying, Ge Jierong, Feng Qing
Department of Nutrition and Food Hygiene, Key Laboratory of Toxicology, School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
Toxics. 2025 May 1;13(5):369. doi: 10.3390/toxics13050369.
Environmental pollution significantly exacerbates various diseases, particularly those affecting the cardiovascular and respiratory systems. Our previous studies have shown that acrolein, an environmental pollutant, promotes atherosclerosis by downregulating the circadian clock genes (CLOCK/BMAL1) and disrupting circadian rhythm. We have also found that intermittent fasting (IF), closely linked to the circadian clock, may mitigate atherosclerosis induced by acrolein. Ferroptosis, a newly identified form of regulated cell death, is associated with the acceleration of atherosclerotic development, but its relationship with the circadian clock is not well understood. In this study, we explored the potential of IF to alleviate ferroptosis by modulating the circadian clock. Our in vivo experiments revealed that IF reversed ferroptosis and upregulated CLOCK/BMAL1 in APOE-/- mice. In human umbilical vein endothelial cells (HUVECs), we discovered that acrolein-induced ferroptosis leads to cell death, while short-term starvation (STS, IF cell model) reversed this effect. Acrolein also suppressed the expression of AMP-activated protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), and CLOCK/BMAL1, which were restored by subsequent STS treatments. Additionally, the overexpression of CLOCK/BMAL1 mitigated ferroptosis, consistent with findings from CLOCK gene knockout experiments. Notably, CLOCK/BMAL1 and AMPK/NRF2 were found to be mutually regulated. Concurrently, the AMPK and NRF2 signaling pathways may be interdependent and act in concert. In conclusion, our findings suggest that IF modulates the CLOCK/BMAL1-AMPK/NRF2 pathway to alleviate acrolein-induced ferroptosis, offering a potential strategy to address health issues related to environmental pollution.
环境污染会显著加剧各种疾病，尤其是那些影响心血管和呼吸系统的疾病。我们之前的研究表明，环境污染物丙烯醛通过下调生物钟基因（CLOCK/BMAL1）和扰乱昼夜节律来促进动脉粥样硬化。我们还发现，与生物钟密切相关的间歇性禁食（IF）可能减轻丙烯醛诱导的动脉粥样硬化。铁死亡是一种新发现的程序性细胞死亡形式，与动脉粥样硬化发展的加速有关，但其与生物钟的关系尚不清楚。在本研究中，我们探讨了IF通过调节生物钟来减轻铁死亡的潜力。我们的体内实验表明，IF可逆转APOE-/-小鼠的铁死亡并上调CLOCK/BMAL1。在人脐静脉内皮细胞（HUVECs）中，我们发现丙烯醛诱导的铁死亡导致细胞死亡，而短期饥饿（STS，IF细胞模型）可逆转这种效应。丙烯醛还抑制了AMP激活的蛋白激酶（AMPK）、核因子红细胞2相关因子2（NRF2）和CLOCK/BMAL1的表达，随后的STS处理可使其恢复。此外，CLOCK/BMAL1的过表达减轻了铁死亡，这与CLOCK基因敲除实验的结果一致。值得注意的是，发现CLOCK/BMAL1与AMPK/NRF2相互调节。同时，AMPK和NRF2信号通路可能相互依赖并协同作用。总之，我们的研究结果表明，IF通过调节CLOCK/BMAL1-AMPK/NRF2通路来减轻丙烯醛诱导的铁死亡，为解决与环境污染相关的健康问题提供了一种潜在策略。
