低氧诱导因子1（HIF-1）是一种通过感知氧气水平来调控转录水平的因子，从而协调细胞对缺氧的适应性反应。多项研究表明，有毒金属接触也可能调节HIF-1α信号传导途径，尽管现有数据较少。因此，本综述旨在总结有关有毒金属对HIF-1信号传导的影响和潜在机制的现有数据，重点关注有毒金属的氧化剂效应。这些金属的特定影响效果取决于不同的细胞类型，并可导致HIF-1通路的上调或下调。HIF-1信号通路的抑制可能导致缺氧耐受性和适应性下降，从而促进细胞的缺氧损伤。相反，由金属诱导的激活可能通过促进血管生成，从而增加对缺氧的耐受性，从而促进肿瘤生长和造成重金属致癌的影响。Cr、As和Ni的暴露主要表现为HIF-1通路上调，而Cd和Hg则可能同时刺激和抑制HIF-1通路。有毒金属暴露对HIF-1信号通路影响的机制涉及脯氨酸羟化酶（PHD2）活性的调节以及与其他密切相关途径的干扰，包括Nrf2、PI3K/Akt、NF-κB和MAPK信号传导。这些效应至少部分通过金属诱导的ROS生成介导。从假设上讲，通过直接（PHD2调节）或间接（抗氧化剂）机制维持足够的HIF-1信号通路，在有毒金属暴露下可能提供预防金属毒性不良影响的额外策略。© 2023年，作者独家授权Springer-Verlag GmbH Germany（Springer Nature的一部分）。

Hypoxia-inducible factor 1 (HIF-1) is an oxygen-sensing transcriptional regulator orchestrating a complex of adaptive cellular responses to hypoxia. Several studies have demonstrated that toxic metal exposure may also modulate HIF-1α signal transduction pathway, although the existing data are scarce. Therefore, the present review aims to summarize the existing data on the effects of toxic metals on HIF-1 signaling and the potential underlying mechanisms with a special focus on prooxidant effect of the metals. The particular effect of metals was shown to be dependent on cell type, varying from down- to up-regulation of HIF-1 pathway. Inhibition of HIF-1 signaling may contribute to impaired hypoxic tolerance and adaptation, thus promoting hypoxic damage in the cells. In contrast, its metal-induced activation may result in increased tolerance to hypoxia through increased angiogenesis, thus promoting tumor growth and contributing to carcinogenic effect of heavy metals. Up-regulation of HIF-1 signaling is mainly observed upon Cr, As, and Ni exposure, whereas Cd and Hg may both stimulate and inhibit HIF-1 pathway. The mechanisms underlying the influence of toxic metal exposure on HIF-1 signaling involve modulation of prolyl hydroxylases (PHD2) activity, as well as interference with other tightly related pathways including Nrf2, PI3K/Akt, NF-κB, and MAPK signaling. These effects are at least partially mediated by metal-induced ROS generation. Hypothetically, maintenance of adequate HIF-1 signaling upon toxic metal exposure through direct (PHD2 modulation) or indirect (antioxidant) mechanisms may provide an additional strategy for prevention of adverse effects of metal toxicity.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.