IL-13 facilitates ferroptotic death in asthmatic epithelial cells via SOCS1-mediated ubiquitinated degradation of SLC7A11
Manli Miao,
Min Pan,
Xu Chen,
Jiapan Shen,
Ling Zhang,
Xiaoxia Feng,
Mengting Chen,
Guofeng Cui,
Huaiyuan Zong,
Wen Zhang,
Shuang Chang,
Fangzhou Xu,
Zixi Wang,
Dapeng Li,
Weiwei Liu,
Zhao Ding,
Shengquan Zhang,
Biao Chen,
Xiaojun Zha,
Xiaoyun Fan
Affiliations
Manli Miao
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China; Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Jining Medical University, Jining, China
Min Pan
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Xu Chen
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Jiapan Shen
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Ling Zhang
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Xiaoxia Feng
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Mengting Chen
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Guofeng Cui
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Huaiyuan Zong
Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
Wen Zhang
Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, China
Shuang Chang
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Fangzhou Xu
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China
Zixi Wang
Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
Dapeng Li
Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Department of Otolaryngology, Head and Neck Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
Weiwei Liu
Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
Zhao Ding
Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
Shengquan Zhang
Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
Biao Chen
Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, China; Corresponding author.
Xiaojun Zha
Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Corresponding author.
Xiaoyun Fan
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China; Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, China; Corresponding author. Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
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.
