Jomova Klaudia, Alomar Suliman Y, Valko Richard, Nepovimova Eugenie, Kuca Kamil, Valko Marian
Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia.
Doping Research Chair, Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
EXCLI J. 2025 Jul 25;24:880-954. doi: 10.17179/excli2025-8449. eCollection 2025.
Given the key importance played by the redox-active metals iron (Fe), copper (Cu), and manganese (Mn) in vital cellular processes, such as DNA synthesis, oxidative phosphorylation, the detoxification of reactive oxygen species (ROS), and angiogenesis, it is not surprising that their dysregulation plays a causative role in many human diseases. The same applies to redox-inactive zinc (Zn), which is involved in numerous biological functions, and serves as a structural element, a catalyst, and a participant in both intracellular and intercellular signaling and in maintaining immune system function. An imbalance in redox active (Fe, Cu, Mn) or redox inactive (Zn) metal ions, whether in excess or deficiency, is harmful and may disrupt the structural, regulatory, and catalytic roles of various antioxidant enzymes (superoxide dismutases (SODs), catalase (CAT), glutathione peroxidases (GPxs)), proteins, receptors, transporters, alter sulfhydryl homeostasis, generate high levels of ROS (e.g., hydroxyl radicals by the Fenton reaction), initiate lipid peroxidation, cause DNA damage, and lead to cell death via mechanisms such as ferroptosis, cuproptosis, cellular senescence, or inflammation. Maintaining redox homeostasis is essential for regulating numerous cellular signaling pathways. Redox-sensitive signaling pathways, such as the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase kinase (MAPK), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, form an intricate network that governs cellular responses to redox metal-induced oxidative stress and inflammation. The Nrf2 pathway is primarily responsible for mediating antioxidant defenses, whereas the NF-κB and MAPK pathways play roles in proinflammatory and stress-related responses. Dysregulation of redox-active Fe, Cu, Mn, and redox-inactive Zn can alter epigenetic regulatory mechanisms such as DNA methylation, histone modification, and non-coding RNA expression. The dyshomeostasis of metal ions is closely related to the pathogenesis of lung, renal, and gastrointestinal diseases, neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, and Huntington's disease), psychiatric conditions (schizophrenia), and various cancers. This review summarizes recent findings on the role of iron, copper, manganese, and zinc in maintaining physiological functions, redox homeostasis, and human diseases. See also the graphical abstract(Fig. 1).
鉴于氧化还原活性金属铁（Fe）、铜（Cu）和锰（Mn）在重要细胞过程（如DNA合成、氧化磷酸化、活性氧（ROS）解毒和血管生成）中发挥的关键作用，它们的失调在许多人类疾病中起致病作用也就不足为奇了。这同样适用于氧化还原惰性锌（Zn），它参与众多生物学功能，并作为结构元素、催化剂以及细胞内和细胞间信号传导及维持免疫系统功能的参与者。氧化还原活性（Fe、Cu、Mn）或氧化还原惰性（Zn）金属离子的失衡，无论是过量还是缺乏，都是有害的，可能会破坏各种抗氧化酶（超氧化物歧化酶（SODs）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GPxs））、蛋白质、受体、转运蛋白的结构、调节和催化作用，改变巯基稳态，产生高水平的ROS（例如通过芬顿反应产生羟基自由基），引发脂质过氧化，导致DNA损伤，并通过铁死亡、铜死亡、细胞衰老或炎症等机制导致细胞死亡。维持氧化还原稳态对于调节众多细胞信号通路至关重要。氧化还原敏感信号通路，如核因子κB（NF-κB）、丝裂原活化蛋白激酶激酶（MAPK）和核因子红细胞2相关因子2（Nrf2）通路，形成一个复杂的网络，控制细胞对氧化还原金属诱导的氧化应激和炎症的反应。Nrf2通路主要负责介导抗氧化防御，而NF-κB和MAPK通路在促炎和应激相关反应中发挥作用。氧化还原活性Fe、Cu、Mn和氧化还原惰性Zn的失调可改变表观遗传调控机制，如DNA甲基化、组蛋白修饰和非编码RNA表达。金属离子的动态平衡失调与肺、肾和胃肠道疾病、神经退行性疾病（阿尔茨海默病、帕金森病和亨廷顿病）、精神疾病（精神分裂症）以及各种癌症的发病机制密切相关。本综述总结了关于铁、铜、锰和锌在维持生理功能、氧化还原稳态及人类疾病中作用的最新发现。另见图1的图形摘要。
