Diabetic nephropathy is a common microvascular complication of diabetes mellitus and one of the main causes of death in patients with diabetes mellitus. Ferroptosis is a newly discovered iron-dependent regulated cell death, which may contribute to the pathogenesis and development of diabetic nephropathy. Adenosine monophosphate-activated protein kinase (AMPK)-mediated ferroptosis-related signaling pathways can slow down the progression of diabetic nephropathy, but excessive activation of AMPK signaling pathway may induce cells to undergo autophagic death. Activation of the signaling pathway mediated by nuclear factor-erythroid 2-related factor (Nrf) 2 and heme oxygenase (HO)-1 can inhibit ferroptosis of cells and alleviate diabetic nephropathy. However, the regulatory effect of HO-1 on ferroptosis is bidirectional, and activation of HIF-1α/HO-1 pathway may lead to intracellular iron overload and ultimately promote ferroptosis. Transforming growth factor (TGF)-β1 mediated signaling pathways can accelerate lipid peroxidation by down-regulating the levels of SLC7A11/GSH/GPX4. The ferroptosis-related signaling pathways mediated by exosome lncRNAs/circRNAs/miRNAs are also involved in the pathogenesis and development of diabetic nephropathy. In addition, signaling pathways mediated by stimulator of interferon gene (STING) and the novel ferroptosis promoter acyl-CoA synthetase long-chain family (ACSL) 1 can induce ferroptosis to promote the progression of diabetic nephropathy. In this review, we focus on the roles of ferroptosis in diabetic nephropathy through the signaling pathways mediated by AMPK, Nrf2/HO-1, TGF-β and exosomes, to elaborate the pathogenesis and development of diabetic nephropathy, and the potential therapeutic target for diabetic nephropathy.
糖尿病肾病是常见的糖尿病微血管并发症，也是糖尿病患者死亡的主要原因之一。铁死亡是一种铁依赖性调节性细胞死亡，其在糖尿病肾病的发生发展中具有一定作用。腺苷一磷酸活化的蛋白质激酶（AMPK）介导的铁死亡相关信号通路可以延缓糖尿病肾病的进程，但AMPK信号过度激活可能会诱导细胞发生自噬性死亡；激活核转录因子红系2相关因子（Nrf）2和血红素加氧酶（HO）-1介导的信号通路能够抑制细胞铁死亡并改善糖尿病肾病，但HO-1在铁死亡中的调节作用是双向的，激活HIF-1α/HO-1信号通路可能导致细胞内铁过载，最终促进铁死亡；转化生长因子（TGF）-β1介导的信号通路通过下调SLC7A11/GSH/GPX4的表达加快细胞脂质过氧化；外泌体lncRNA/circRNA/miRNA介导的铁死亡相关信号通路也参与了糖尿病肾病的发生发展；此外，新型铁死亡启动子酰基辅酶A合成酶长链家族1以及干扰素基因刺激因子等介导的信号通路可诱导细胞铁死亡从而加速糖尿病肾病的进程。本文重点阐述了铁死亡通过AMPK、Nrf2/HO-1、TGF-β和外泌体等介导的信号通路在糖尿病肾病中发挥重要作用，以期为阐明糖尿病肾病的病理机制提供新的依据，为有效治疗糖尿病肾病提供新的靶点。.
Keywords: Cell death; Diabetic nephropathy; Ferroptosis; Review; Signaling pathway.