Key Laboratory of Drug Targeting and Drug Delivery Systems of Ministry of Education, West China School of Pharmacy, College of Polymer Science and Engineering , Sichuan University , Chengdu 610065 , China.
Nano Lett. 2019 Nov 13;19(11):7781-7792. doi: 10.1021/acs.nanolett.9b02795. Epub 2019 Oct 2.
Though plastic nanoparticles have already raised much concern for their potential impact on health, our understanding of their biological effects is still utterly limited. Here we demonstrate for the first time that carboxyl-modified polystyrene nanoparticles (CPS) could effectively inhibit ferroptosis as a result of reduced cellular ROS which was triggered by transcription factor EB (TFEB) nucleus translocation. In this process, CPS first entered cells via macropinocytosis, then CPS-containing macropinosomes fused with lysosomes and expanded into abnormal lysosome-like large vacuoles in vacuolar-type H-ATPase (V-ATPase) and aquaporins (AQPs) in a dependent way. These large vacuoles were detected both in vitro and in vivo, which was found to be a sign of lysosome stress. The lysosome stress induced deactivation of mammalian target of rapamycin (mTOR) which led to nucleus translocation of TFEB. Then, TFEB-dependent enhanced expression of lysosomal proteins and superoxide dismutase (SOD) which ultimately led to ROS reduction and inhibition of ferroptosis. Knockout of TFEB-enhanced ferroptosis was triggered by Erastin and abolished the effect of CPS on ROS and ferroptosis. In summary, our results reveal a novel mechanism whereby CPS reduced ROS and inhibited ferroptosis in a TFEB-dependent way. These findings have important implications for understanding the biological effects of polystyrene nanoparticles and searching for new anti-ROS and antiferroptosis particles or reagents.
尽管塑料纳米颗粒已经因其潜在的健康影响而引起了广泛关注，但我们对其生物效应的理解仍然非常有限。在这里，我们首次证明，羧基化聚苯乙烯纳米颗粒（CPS）可以通过转录因子 EB（TFEB）核转位触发的细胞 ROS 减少来有效抑制铁死亡。在这个过程中，CPS 首先通过巨胞饮作用进入细胞，然后 CPS 包含的巨胞饮体与溶酶体融合，并在液泡型 H+-ATP 酶（V-ATPase）和水通道蛋白（AQPs）的依赖性下扩展成异常的溶酶体样大空泡。在体外和体内都检测到了这些大空泡，这是溶酶体应激的一个标志。溶酶体应激导致哺乳动物雷帕霉素靶蛋白（mTOR）失活，从而导致 TFEB 核转位。然后，TFEB 依赖性增强了溶酶体蛋白和超氧化物歧化酶（SOD）的表达，最终导致 ROS 减少和铁死亡抑制。用 Erastin 敲除 TFEB 会触发增强的铁死亡，并消除 CPS 对 ROS 和铁死亡的影响。总之，我们的结果揭示了一种新的机制，即 CPS 通过 TFEB 依赖性方式降低 ROS 并抑制铁死亡。这些发现对理解聚苯乙烯纳米颗粒的生物效应以及寻找新的抗 ROS 和抗铁死亡颗粒或试剂具有重要意义。
