Research advances in mechanisms of ferroptosis in air pollution-related diseases
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摘要:
流行病学研究证实，大气污染物暴露会导致人体不良健康结局，但具体的生物学机制尚不明确。空气污染暴露后，氧化应激已被证实是影响健康的经典调控机制。近年来研究发现，氧化应激导致的脂质过氧化与铁累积共同作用，可诱导调节性细胞死亡，被称为“铁死亡”。因此，铁死亡可能是空气污染物引发不良健康结局的重要机制。为了探究空气污染引发不良健康结局的铁死亡机制，基于已有研究成果，梳理了铁死亡在空气污染导致不良健康结局中的作用靶点，详细探讨了空气污染物诱导铁死亡的调控机制。系统综述结果表明：细颗粒物（PM2.5）、臭氧(ozone，O3)、香烟烟雾（cigarette smoke，CS）均可通过影响铁代谢和脂质过氧化途径中的关键基因诱发铁死亡；大气污染物对铁死亡的调控过程主要是通过引发氧化应激降低机体抗氧化能力，从而降低铁死亡的抗性。本综述结果进一步补充了空气污染诱导疾病的发生机制，可为潜在的疾病治疗策略提供理论支持。
Abstract:Epidemiologic studies have confirmed that air pollutants exposure could result in various adverse health outcomes, but the specific biological mechanism is still unclear. Oxidative stress (OS) induced by air pollution exposure has been confirmed as a classical regulatory mechanism that affects our health. In recent years, it has been found that the combined effect of lipid peroxidation induced by OS and iron accumulation can induce programmed cell death, which has been termed "ferroptosis". Thus, ferroptosis could be an important regulatory mechanism of adverse health outcomes induced by air pollutants exposure. To explore the mechanisms by which air pollution triggers ferroptosis, we reviewed and summarized the targets and regulatory mechanisms of ferroptosis in regulating adverse health outcomes caused by air pollution, based on existing research results. The result showed that fine particulate matter (PM2.5), ozone (O3) and cigarette smoke (CS) could induce ferroptosis by affecting key genes in iron metabolism and lipid peroxidation pathways. In a word, air pollutants could cause OS and reduce the antioxidant capacity, then reduce the resistance of ferroptosis. This review further supplemented the mechanism of air pollution-induced diseases, which could provide theoretical support for potential disease treatment strategies.
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Key words:
- air pollution /
- ferroptosis /
- health effects /
- regulatory mechanisms
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图 1 铁死亡的调控机制示意
TFRC—转铁蛋白；LOX—脂氧合酶；POR—细胞色素P450还原酶；ACSL4—酰基辅酶A合成酶长链家族成员4；LPCAT3—溶血磷脂酰基转移酶3；Cys2—胱氨酸；Cys—半胱氨酸；GCL—谷氨酸-半胱氨酸连接酶；GSS—谷胱甘肽合酶；GSH—还原型谷胱甘肽；GSSG—氧化型谷胱甘肽；GPX4—谷胱甘肽过氧化物酶4。
Figure 1. Mechanisms of ferroptosis regulation
表 1 铁死亡在不同空气污染物诱导不良健康结局中的研究进展
Table 1. Progress of ferroptosis in the induction of adverse health outcomes by different air pollutants
污染物 不良结局 作用机制 信号通路 细颗粒物（PM2.5） 呼吸系统疾病 通过诱导细胞和线粒体ROS的产生，导致氧化应激失衡，引起一系列铁死亡过程[38-45]，并且可以激活FSP1、Nrf2[46]、PI3K/Akt通路[47] xCT/SLC7A11，GPX4，FTH1，FTL，TfR1，
FSP1，PI3K/Akt/Nrf2，HO-1心血管系统疾病 铁死亡在PM2.5诱导心肌细胞损伤的机制中起着重要作用[48-49] xCT/SLC7A11，GPX4，TfR1，FTL，FTH1，
YY1，NCOA4神经系统疾病 暴露于PM2.5可能改变癫痫发作患者铁死亡相关的基因表达，并加重癫痫发作诱发的认知缺陷[50-51]，且对视神经造成损害[52] GPX4，FTH1，NF-κB/Nrf2 生殖系统疾病 PM2.5对幼年雄性大鼠精子生成功能产生影响，其中线粒体功能障碍和铁死亡是重要机制[53-54] GPX4，SLC7A11，FPN1，DMT1，
Keap1，Acsl4，Aloxe3消化系统疾病 暴露于PM2.5会增加Nrf2和HO-1的水平，并且使得Keap1下调，产生ROS诱导小肠上皮细胞铁死亡[55] Nrf2，HO-1，Keap1，
GPX4，xCT臭氧（O3） 心血管系统疾病 臭氧预处理增强了Nrf2的核易位，抑制了铁死亡，通过Nrf2/SLC7A11/GPX4信号通路保护心肌免受I/R损伤[56] Nrf2/SLC7A11/GPX4 呼吸系统疾病 臭氧通过激活TRPA1诱导人体支气管上皮细胞和小鼠肺线粒体功能障碍，从而通过PI3K/Akt/OPA1轴导致铁死亡[57] PI3K/Akt，OPA1,
ACSL4，SLC7A11，GPX4，
TFR1，TRPA1神经系统疾病 臭氧可以通过NRF2/SLC7A11/GPX4 通路改善脑缺血再灌注损伤[58] ACSL4，SLC7A11，GPX4，
FTH1香烟烟雾 （CS） 生殖系统疾病 CS暴露损害卵巢卵泡储备可能是由于颗粒样细胞中的氧化还原失衡引起的[59] GPX1，Wnt10b， Gja1，Lama1，GPX4 
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