Patulin (PAT) is a common food-borne mycotoxin with diverse toxic effects including nephrotoxicity. The induction of oxidative stress is suggested to be a key mechanism contributed to toxicities of PAT. Reduced glutathione (GSH), a sulfhydryl-containing tripeptide, is a key reason for PAT-mediated oxidative stress. Cystine/glutamate antiporter (system x_c⁻)-mediated cystine uptake plays a critical role in maintaining redox balance via promoting GSH biosynthesis. In this study, we addressed if GSH reduction by PAT was associated with inhibition of system x_c⁻-mediated GSH biosynthesis. Results showed that PAT significantly decreased activity of SLC7A11, a core subunit of system x_c⁻, through activating AMPK-mediated formation of beclin1-SLC7A11 complex. Furthermore, PAT promoted ferroptosis induced by a known ferroptosis inducer RSL3 in normal renal cells, and exacerbated folic acid-induced nephrotoxicity in a mouse model of acute kidney injury. The findings of the present study provide new insights into PAT-induced kidney toxicity, and implicate that patients with ferroptosis-associated diseases maybe more susceptible to PAT.

棒曲霉素 (PAT) 是一种常见的食源性霉菌毒素，具有多种毒性作用，包括肾毒性。氧化应激的诱导被认为是导致 PAT 毒性的关键机制。还原型谷胱甘肽 (GSH) 是一种含巯基的三肽，是 PAT 介导的氧化应激的关键原因。胱氨酸/谷氨酸逆向转运体（系统 x _c ^-）介导的胱氨酸摄取通过促进 GSH 生物合成在维持氧化还原平衡中起关键作用。在这项研究中，我们讨论了 PAT 对 GSH 的减少是否与系统 x _c ^-介导的 GSH 生物合成的抑制有关。结果表明，PAT 显着降低了系统 x _{c的核心亚基 SLC7A11 的活性}^-，通过激活 AMPK 介导的 beclin1-SLC7A11 复合物的形成。此外，PAT 促进了正常肾细胞中由已知的铁死亡诱导剂 RSL3 诱导的铁死亡，并在急性肾损伤小鼠模型中加剧了叶酸诱导的肾毒性。本研究的结果为 PAT 诱导的肾毒性提供了新的见解，并暗示患有铁死亡相关疾病的患者可能更容易受到 PAT 的影响。