Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.

中文翻译：

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IL-13 通过 SOCS1 介导的 SLC7A11 泛素化降解促进哮喘上皮细胞铁死亡


Th2 高哮喘的特点是 2 型细胞因子水平升高，例如白细胞介素 13 (IL-13)，其患病率在全球范围内不断增加。铁死亡是最近发现的一种程序性细胞死亡类型，参与Th2高哮喘的病理过程。然而，其根本机制仍不完全清楚。在这项研究中，我们证明了哮喘患者的血清丙二醛 (MDA) 水平（脂质过氧化指数）与 IL-13 水平呈正相关，与预测的 1 秒用力呼气量 (FEV1%) 呈负相关。此外，通过分析永生化气道上皮细胞、人气道类器官和卵清蛋白 (OVA) 激发的哮喘模型，我们发现 IL-13 通过上调细胞因子信号传导抑制因子 1 (SOCS1) 来促进铁死亡。我们发现信号转导子和转录激活子 6 (STAT6) 在 IL-13 刺激下促进 SOCS1 的转录。此外，E3泛素连接酶SOCS1被发现与溶质载体家族7成员11（SLC7A11）结合并催化其泛素化降解，从而促进气道上皮细胞铁死亡。最后，我们发现抑制 SOCS1 可以减少 OVA 攻击的宽型小鼠气道上皮细胞的铁死亡并减轻气道高反应性 (AHR)，而 SOCS1 过表达在 OVA 攻击的 IL-13 敲除小鼠中加剧上述情况。我们的研究结果表明，IL-13/STAT6/SOCS1/SLC7A11 通路是 Th2 高哮喘中铁死亡的一种新分子机制，证实靶向气道上皮细胞铁死亡是 Th2 高哮喘的潜在治疗策略。