BMAL1缺乏通过促进JUN介导的脂质过氧化和气道上皮铁死亡而加剧尘螨诱导的哮喘
2026/07/31
摘要
哮喘表现出显著的昼夜节律变化，但连接生物钟紊乱与气道上皮损伤的分子机制尚不清楚。在本研究中，我们确定核心生物钟组分BMAL1是过敏性气道炎症期间限制铁死亡相关损伤的关键上皮调节因子。利用尘螨（HDM）诱导的小鼠哮喘模型和HDM刺激的人支气管上皮细胞，我们发现BMAL1表达显著降低，而BMAL1缺乏明显加重气道炎症、黏液化生和重塑。整合转录组学和代谢组学分析揭示了与铁死亡相关的炎症激活和代谢重编程特征。一致地，在体内和体外，BMAL1缺乏均增加了气道上皮的脂质过氧化和活性氧水平，下调GPX4和xCT（SLC7A11），并上调COX2表达。用铁死亡抑制剂Ferrostatin-1处理可减轻这些改变，并部分挽救Bmal1缺陷小鼠中加重的哮喘表型。值得注意的是，BMAL1的组成性过表达也会加重HDM诱导的气道病理，提示BMAL1节律振荡的破坏有助于疾病进展。从机制上讲，BMAL1缺乏激活AP-1通路，诱导COX2表达，并促进铁死亡相关上皮损伤，而JUN的抑制可缓解这种表型。此外，褪黑素也减轻了与BMAL1缺乏相关的加重气道病理和铁死亡相关变化。总之，这些发现确定BMAL1是气道上皮铁死亡的关键调节因子，并强调JUN信号以及与COX2相关的前列腺素反应是由昼夜节律失调驱动的哮喘加重的下游组分。
BMAL1 deficiency exacerbates HDM-induced asthma by promoting JUN-mediated lipid peroxidation and airway epithelial ferroptosis
Yixin Chen, Haohua Huang, Zihan Chen, Minxuan Hu, Jinming Zhang, Qi Yu, Dongyu Liu, Huimin Yang, Yuhan Du, Yanqun Li, Shiya Liang, Wen Li, Wufeng Huang, Hua Liao, Jieyu Wu, Hangming Dong
Abstract
Asthma exhibits pronounced circadian variation, yet the molecular mechanisms linking clock disruption to airway epithelial injury remain unclear. In this study, we identify the core clock component BMAL1 as a critical epithelial regulator that restrains ferroptosis-associated injury during allergic airway inflammation. Using a house dust mite (HDM)-induced murine asthma model and HDM-stimulated human bronchial epithelial cells, we found that BMAL1 expression was significantly reduced, whereas BMAL1 deficiency markedly aggravated airway inflammation, mucus metaplasia, and remodeling. Integrated transcriptomic and metabolomic analyses revealed a signature of inflammatory activation and metabolic reprogramming linked to ferroptosis. Consistently, BMAL1 deficiency increased lipid peroxidation and reactive oxygen species levels, downregulated GPX4 and xCT (SLC7A11), and upregulated COX2 expression in the airway epithelium both in vivo and in vitro. Treatment with Ferrostatin-1 attenuated these alterations and partially rescued the aggravated asthmatic phenotype in Bmal1-deficient mice. Notably, constitutive overexpression of BMAL1 also worsened HDM-induced airway pathology, suggesting that disruption of BMAL1 rhythmic oscillation contributes to disease progression. Mechanistically, BMAL1 deficiency activated the AP-1 pathway, induced COX2 expression, and promoted ferroptosis-associated epithelial injury, whereas inhibition of JUN alleviated this phenotype. Furthermore, melatonin also mitigated the aggravated airway pathology and ferroptosis-related changes associated with BMAL1 deficiency. Collectively, these findings identify BMAL1 as a key regulator of airway epithelial ferroptosis and highlight JUN signaling, together with COX2-associated prostaglandin responses, as downstream components of asthma exacerbations driven by circadian dysregulation.
哮喘表现出显著的昼夜节律变化，但连接生物钟紊乱与气道上皮损伤的分子机制尚不清楚。在本研究中，我们确定核心生物钟组分BMAL1是过敏性气道炎症期间限制铁死亡相关损伤的关键上皮调节因子。利用尘螨（HDM）诱导的小鼠哮喘模型和HDM刺激的人支气管上皮细胞，我们发现BMAL1表达显著降低，而BMAL1缺乏明显加重气道炎症、黏液化生和重塑。整合转录组学和代谢组学分析揭示了与铁死亡相关的炎症激活和代谢重编程特征。一致地，在体内和体外，BMAL1缺乏均增加了气道上皮的脂质过氧化和活性氧水平，下调GPX4和xCT（SLC7A11），并上调COX2表达。用铁死亡抑制剂Ferrostatin-1处理可减轻这些改变，并部分挽救Bmal1缺陷小鼠中加重的哮喘表型。值得注意的是，BMAL1的组成性过表达也会加重HDM诱导的气道病理，提示BMAL1节律振荡的破坏有助于疾病进展。从机制上讲，BMAL1缺乏激活AP-1通路，诱导COX2表达，并促进铁死亡相关上皮损伤，而JUN的抑制可缓解这种表型。此外，褪黑素也减轻了与BMAL1缺乏相关的加重气道病理和铁死亡相关变化。总之，这些发现确定BMAL1是气道上皮铁死亡的关键调节因子，并强调JUN信号以及与COX2相关的前列腺素反应是由昼夜节律失调驱动的哮喘加重的下游组分。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译）
（中日友好医院呼吸与危重症医学科 林江涛 审校）
（Redox Biol. 2026 Jul 18:96:104312.doi: 10.1016/j.redox.2026.104312.）
（中日友好医院呼吸与危重症医学科 林江涛 审校）
（Redox Biol. 2026 Jul 18:96:104312.doi: 10.1016/j.redox.2026.104312.）
BMAL1 deficiency exacerbates HDM-induced asthma by promoting JUN-mediated lipid peroxidation and airway epithelial ferroptosis
Yixin Chen, Haohua Huang, Zihan Chen, Minxuan Hu, Jinming Zhang, Qi Yu, Dongyu Liu, Huimin Yang, Yuhan Du, Yanqun Li, Shiya Liang, Wen Li, Wufeng Huang, Hua Liao, Jieyu Wu, Hangming Dong
Abstract
Asthma exhibits pronounced circadian variation, yet the molecular mechanisms linking clock disruption to airway epithelial injury remain unclear. In this study, we identify the core clock component BMAL1 as a critical epithelial regulator that restrains ferroptosis-associated injury during allergic airway inflammation. Using a house dust mite (HDM)-induced murine asthma model and HDM-stimulated human bronchial epithelial cells, we found that BMAL1 expression was significantly reduced, whereas BMAL1 deficiency markedly aggravated airway inflammation, mucus metaplasia, and remodeling. Integrated transcriptomic and metabolomic analyses revealed a signature of inflammatory activation and metabolic reprogramming linked to ferroptosis. Consistently, BMAL1 deficiency increased lipid peroxidation and reactive oxygen species levels, downregulated GPX4 and xCT (SLC7A11), and upregulated COX2 expression in the airway epithelium both in vivo and in vitro. Treatment with Ferrostatin-1 attenuated these alterations and partially rescued the aggravated asthmatic phenotype in Bmal1-deficient mice. Notably, constitutive overexpression of BMAL1 also worsened HDM-induced airway pathology, suggesting that disruption of BMAL1 rhythmic oscillation contributes to disease progression. Mechanistically, BMAL1 deficiency activated the AP-1 pathway, induced COX2 expression, and promoted ferroptosis-associated epithelial injury, whereas inhibition of JUN alleviated this phenotype. Furthermore, melatonin also mitigated the aggravated airway pathology and ferroptosis-related changes associated with BMAL1 deficiency. Collectively, these findings identify BMAL1 as a key regulator of airway epithelial ferroptosis and highlight JUN signaling, together with COX2-associated prostaglandin responses, as downstream components of asthma exacerbations driven by circadian dysregulation.
上一篇：
哮喘患者鼻上皮细胞中CC16介导的宿主对鼻病毒的反应受损
下一篇：
气道上皮细胞中FOXA1介导的CEPT1缺失通过内质网应激-线粒体功能障碍轴驱动哮喘发生发展
