Lee Jin-Yong, Tokumoto Maki, Satoh Masahiko
Laboratory of Public Health, School of Pharmacy, Aichi Gakuin University, Kusumoto-cho 1-100, Chikusa-ku, Nagoya 464-8650, Japan.
Int J Mol Sci. 2025 Aug 4;26(15):7515. doi: 10.3390/ijms26157515.
Cadmium (Cd) is a toxic environmental heavy metal that exerts harmful effects on multiple tissues, including the kidney, liver, lung, and bone, and is also associated with the development of anemia. However, the precise molecular mechanisms underlying Cd-induced toxicity remain incompletely understood. In this paper, we review the recent molecular mechanisms of Cd-induced toxicity and its modification, with a particular emphasis on our recent findings. Using a combination of DNA microarray analysis, protein-DNA binding assays, and siRNA-mediated gene silencing, we identified several transcription factors, YY1, FOXF1, ARNT, and MEF2A, as novel molecular targets of Cd. The downregulation of their downstream genes, including , , , and , was directly associated with the expression of cytotoxicity. In addition, PPARδ plays a pivotal role in modulating cellular susceptibility to Cd-induced renal toxicity, potentially by regulating apoptosis-related signaling pathways. In addition to apoptosis pathways, Cd toxicity through ROS generation, ferroptosis and pyroptosis were summarized. Furthermore, it has been revealed that Cd suppresses the expression of iron transport-related genes in duodenal epithelial cells leading to impaired intestinal iron absorption as well as decreased hepatic iron levels. These findings provide a mechanistic basis for Cd-induced iron deficiency anemia, implicating disrupted iron homeostasis as a contributing factor.
镉（Cd）是一种有毒的环境重金属，会对包括肾脏、肝脏、肺和骨骼在内的多种组织产生有害影响，还与贫血的发生有关。然而，Cd诱导毒性的精确分子机制仍未完全清楚。在本文中，我们综述了Cd诱导毒性及其修饰的最新分子机制，特别强调了我们最近的发现。通过结合DNA微阵列分析、蛋白质-DNA结合测定和siRNA介导的基因沉默，我们确定了几种转录因子，即YY1、FOXF1、ARNT和MEF2A，作为Cd的新型分子靶点。它们下游基因的下调，包括[此处原文缺失具体基因名称]、[此处原文缺失具体基因名称]、[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]，与细胞毒性的表达直接相关。此外，PPARδ可能通过调节凋亡相关信号通路，在调节细胞对Cd诱导的肾毒性的易感性中起关键作用。除了凋亡途径，还总结了Cd通过活性氧生成、铁死亡和焦亡产生的毒性。此外，研究发现Cd抑制十二指肠上皮细胞中铁转运相关基因的表达，导致肠道铁吸收受损以及肝脏铁水平降低。这些发现为Cd诱导的缺铁性贫血提供了机制基础，表明铁稳态破坏是一个促成因素。
