抗哮喘药物孟鲁司特通过干扰神经元维甲酸信号通路诱导类孤独症行为
2026/06/30
摘要
孤独症谱系障碍（ASD）影响着全球约1.0%的儿童，且患病率仍呈持续上升趋势。遗传因素对ASD的贡献不足50%，提示非遗传因素在ASD病因学中发挥着关键但尚不明确的作用。本研究发现，孟鲁司特（MTK）——一种半胱氨酰白三烯受体拮抗剂，亦是临床最常用的抗哮喘药物之一——能够强效干扰神经元维甲酸（RA）信号通路，并改变大鼠前额叶皮层（PFC）原代神经元的突触可塑性。产前或出生后早期暴露于孟鲁司特可诱导野生型大鼠出现类孤独症样行为，而补充全反式维甲酸（atRA）可显著缓解上述表型。在人胚胎干细胞来源的脑类器官中，孟鲁司特通过拮抗RA信号通路，损害神经元RA信号传导并改变前脑模式形成。同时，分子对接及生化验证结果强烈提示，孟鲁司特可与维甲酸受体（RARs），特别是维甲酸受体α（RARA）发生物理性相互作用。此外，基于中国大型ASD队列的多中心流行病学调查表明，儿童早期使用孟鲁司特可能确实增加罹患ASD的风险。综上所述，本研究不仅确立了孟鲁司特用药作为人类ASD既往未被认识的危险因素，同时强调了安全用药在ASD预防中的至关重要性。
Anti-asthma drug montelukast induces autistic behaviors via disrupting neuronal retinoic acid signaling.
Zi-Jian, Hao; Qiong-Hui, Wu; Ya-Li, Li;
Abstrast
Autism spectrum disorders (ASD) affect approximately 1.0% of children worldwide with still increasing global prevalence. The fact that genetic factors contribute to less than 50% of ASD suggests some critical yet enigmatic roles of non-genetic factors in ASD etiology. Here, we reported that montelukast (MTK), a cysteinyl leukotriene receptor antagonist and one of the most commonly prescribed anti-asthma drugs, potently disrupted neuronal retinoic acid (RA) signaling and altered synaptic plasticity of the primary neurons from rat pre-frontal cortex (PFC). Prenatal or early postnatal exposure to MTK induced autistic-like behaviors in wild-type rats, which could be significantly alleviated by supplementing all-trans retinoic acid (atRA). MTK altered neuronal RA signaling and forebrain patterning in brain organoids derived from human embryonic stem cells through antagonizing RA in RA signaling. Meanwhile, molecular docking followed by biochemical validation strongly indicated that MTK could physically interact with RA receptors (RARs), e.g. RA receptor α (RARA). Furthermore, multi-center survey with a large Chinese ASD cohort suggested that MTK administration during early childhood might indeed increase the risk of ASD in children. Altogether, our findings have not only established MTK use as a yet unrecognized risk factor for human ASD, but highlighted the key importance of safer use of medicines to prevent ASD.
孤独症谱系障碍（ASD）影响着全球约1.0%的儿童，且患病率仍呈持续上升趋势。遗传因素对ASD的贡献不足50%，提示非遗传因素在ASD病因学中发挥着关键但尚不明确的作用。本研究发现，孟鲁司特（MTK）——一种半胱氨酰白三烯受体拮抗剂，亦是临床最常用的抗哮喘药物之一——能够强效干扰神经元维甲酸（RA）信号通路，并改变大鼠前额叶皮层（PFC）原代神经元的突触可塑性。产前或出生后早期暴露于孟鲁司特可诱导野生型大鼠出现类孤独症样行为，而补充全反式维甲酸（atRA）可显著缓解上述表型。在人胚胎干细胞来源的脑类器官中，孟鲁司特通过拮抗RA信号通路，损害神经元RA信号传导并改变前脑模式形成。同时，分子对接及生化验证结果强烈提示，孟鲁司特可与维甲酸受体（RARs），特别是维甲酸受体α（RARA）发生物理性相互作用。此外，基于中国大型ASD队列的多中心流行病学调查表明，儿童早期使用孟鲁司特可能确实增加罹患ASD的风险。综上所述，本研究不仅确立了孟鲁司特用药作为人类ASD既往未被认识的危险因素，同时强调了安全用药在ASD预防中的至关重要性。
（中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校）
（Signal Transduct Target Ther 2026 Jun 2;11(1).DOI:10.1038/s41392-026-02665-w. IF: 13.493）
（Signal Transduct Target Ther 2026 Jun 2;11(1).DOI:10.1038/s41392-026-02665-w. IF: 13.493）
Anti-asthma drug montelukast induces autistic behaviors via disrupting neuronal retinoic acid signaling.
Zi-Jian, Hao; Qiong-Hui, Wu; Ya-Li, Li;
Abstrast
Autism spectrum disorders (ASD) affect approximately 1.0% of children worldwide with still increasing global prevalence. The fact that genetic factors contribute to less than 50% of ASD suggests some critical yet enigmatic roles of non-genetic factors in ASD etiology. Here, we reported that montelukast (MTK), a cysteinyl leukotriene receptor antagonist and one of the most commonly prescribed anti-asthma drugs, potently disrupted neuronal retinoic acid (RA) signaling and altered synaptic plasticity of the primary neurons from rat pre-frontal cortex (PFC). Prenatal or early postnatal exposure to MTK induced autistic-like behaviors in wild-type rats, which could be significantly alleviated by supplementing all-trans retinoic acid (atRA). MTK altered neuronal RA signaling and forebrain patterning in brain organoids derived from human embryonic stem cells through antagonizing RA in RA signaling. Meanwhile, molecular docking followed by biochemical validation strongly indicated that MTK could physically interact with RA receptors (RARs), e.g. RA receptor α (RARA). Furthermore, multi-center survey with a large Chinese ASD cohort suggested that MTK administration during early childhood might indeed increase the risk of ASD in children. Altogether, our findings have not only established MTK use as a yet unrecognized risk factor for human ASD, but highlighted the key importance of safer use of medicines to prevent ASD.
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