Anti-asthma drug montelukast induces autistic behaviors via disrupting neuronal retinoic acid signaling

Signal Transduction and Targeted Therapy ARTICLE www.nature.com/sigtrans OPEN Anti-asthma drug montelukast induces autistic behaviors via disrupting neuronal retinoic acid signaling 1234567890();,: Zi-Jian Hao1,2,3, Qiong-Hui Wu4,5, Ya-Li Li3, Zhen-Ming Guo6, Zheng-Wei Li3, Gui Wang6, Meng Meng7, Shi-Lin Yuan3, Yilimire Wufuer3, Meng-Huan Zhang6, Jie Chen4, Ting Yang4, Meng-Xia Chen6, Jiang Zhu4, Wang Qi-Hang3,8, Qiu Li4, Shi-Hu Yu3,8, Min Lu4, Hai-Yi Xiong9,10, Yu-Ru Feng4, Meng-Qi Dong11, Jun-Hao Xu12, Jia-Lin Xu13, Li Chen4,5, Han-Ting Yang 14, Jing-Kun Miao9,10, Hong Zhu 15, Bo Yang15,16, Hui-Ying Zhao7,17 ✉, Xiao-Ming Shi18 ✉, Shan Bian 6,19,20,21,22 ✉, Ting-Yu Li4,5 ✉ and Rong-Gui Hu 1,23,24,25,26,27 ✉ 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. Signal Transduction and Targeted Therapy (2026)11:208 ; https://doi.org/10.1038/s41392-026-02665-w 1 Department of Colorectal Surgery and Oncology and School of Brain Science and Brain Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Institute of Science and Technology for Brain-Inspired Intelligence, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China; 3Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; 4Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, National Clinical Research Center for Children and Adolescents’ Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China; 5Growth, Development, and Mental Health of Children and Adolescence Center, Children’s Hospital of Chongqing Medical University, Chongqing, China; 6Institute for Regenerative Medicine, Medical Innovation Centre and State Key Laboratory of Cardiovascular Diseases, Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, National Stem Cell Translational Resource Centre & Ministry of Education Stem Cell Resource Centre, Frontier Science Centre for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China; 7School of Data and Computer Science, Sun Yat-Sen University, Guangzhou, China; 8University of Chinese Academy of Sciences, Beijing, China; 9Department of Pediatrics, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China; 10Department of Pediatrics, Chongqing Health Center for Women and Children, Chongqing, China; 11College of Public Health and Nursing, Shanghai Aurora College, Shanghai, China; 12Department of Biology, Stanford University, Stanford, CA, USA; 13School of Biological Sciences, University of California San Diego, San Diego, CA, USA; 14Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China; 15Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; 16School of Medicine, Hangzhou City University, Hangzhou, China; 17Department of Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China; 18China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China; 19National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China; 20China Regional Research Center, International Center for Genetic Engineering and Biotechnology, Taizhou, China; 21Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji’an, China; 22School of Life Science, Jinggangshan University, Ji’an, China; 23Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China; 24Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou, China; 25Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 26State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China and 27NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou, China Correspondence: Hui-Ying Zhao () or Xiao-Ming Shi () or Shan Bian () or Ting-Yu Li () or Rong-Gui Hu () These authors contributed equally: Zi-Jian Hao, Qiong-Hui Wu, Ya-Li Li, Zhen-Ming Guo, Zheng-Wei Li These authors jointly supervised this work: Hui-Ying Zhao, Xiao-Ming Shi, Shan Bian, Ting-Yu Li, Rong-Gui Hu Received: 26 June 2025 Revised: 2 February 2026 Accepted: 3 March 2026 © The Author(s) 2026 Anti-asthma drug montelukast induces autistic behaviors via disrupting. . . Hao et al. 2 INTRODUCTION Autism spectrum disorder (ASD) comprises a group of complex neurodevelopmental conditions characterized by lifelong behavioral abnormalities, including social defic (...truncated)