Patulin (PAT) is a common mycotoxin, widely found in cereals, seafood, nuts, and especially in fruits and their products. Exposure to this mycotoxin has been reported to induce kidney injury. However, the possible mechanism remains unclear. In our study, short-term high-dose intake of PAT caused acute kidney injury (AKI) in mice. We performed high-throughput transcriptional sequencing to identify differentially expressed genes (DEGs) between the treatment and control groups. The ferroptosis signaling pathway had the highest enrichment, suggesting ferroptosis is involved in PAT-induced AKI. Further, the existence of ferroptosis and autophagy was confirmed by observing the changes of mitochondria morphology and the formation of autophagosomes by electron microscopy. And the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), p62, nuclear receptor coactivator 4 (NCOA4), and ferritin heavy chain 1 (FTH1) were downregulated, whereas acyl-CoA synthase long-chain family member 4 (ACSL4), transferrin (TF), LC3, and ferritin light chain (FTL) expression were upregulated in PAT-exposed mice. These results suggested autophagy-dependent ferroptosis occurred in the animal model. This view has also been confirmed in the human renal tubular epithelial cell (HKC) experiments. Autophagy inhibitor 3-methyladenine (3MA) attenuated PAT-induced ferroptosis and the iron contents in HKC cells. Simultaneous autophagy-dependent ferroptosis can be inhibited by ferroptosis inhibitors ferrostatin-1 (Fer-1) and desferrioxamine (DFO). In general, this study provides a new perspective for exploring the new mechanism of acute kidney injury caused by PAT.

中文翻译：

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棒曲霉素通过自噬-铁死亡通路诱导小鼠急性肾损伤

棒曲霉素 (PAT) 是一种常见的霉菌毒素，广泛存在于谷物、海鲜、坚果中，尤其是水果及其制品中。据报道，接触这种霉菌毒素会导致肾损伤。然而，可能的机制仍不清楚。在我们的研究中，短期大剂量摄入 PAT 会导致小鼠急性肾损伤 (AKI)。我们进行了高通量转录测序，以鉴定治疗组和对照组之间的差异表达基因 (DEG)。铁死亡信号通路的富集度最高，表明铁死亡参与了 PAT 诱导的 AKI。此外，通过电镜观察线粒体形态的变化和自噬体的形成，证实了铁死亡和自噬的存在。以及溶质载体家族 7 成员 11 (SLC7A11) 的表达，谷胱甘肽过氧化物酶 4 (GPX4)、p62、核受体共激活因子 4 (NCOA4) 和铁蛋白重链 1 (FTH1) 下调，而酰基辅酶 A 合酶长链家族成员 4 (ACSL4)、转铁蛋白 (TF)、LC3、在暴露于 PAT 的小鼠中，铁蛋白轻链 (FTL) 的表达上调。这些结果表明在动物模型中发生了自噬依赖性铁死亡。这一观点在人肾小管上皮细胞（HKC）实验中也得到了证实。自噬抑制剂 3-甲基腺嘌呤 (3MA) 减弱了 PAT 诱导的铁死亡和 HKC 细胞中的铁含量。铁死亡抑制剂 ferrostatin-1 (Fer-1) 和去铁胺 (DFO) 可以抑制同时发生的自噬依赖性铁死亡。总体而言，本研究为探索PAT致急性肾损伤的新机制提供了新的视角。