2. Academic Validation
  3. A novel lncRNA, lncMCL1, modulates neural pyroptosis associated with epilepsy via stabilizing DDX3X

A novel lncRNA, lncMCL1, modulates neural pyroptosis associated with epilepsy via stabilizing DDX3X

  • Cell Death Differ. 2025 Sep 22. doi: 10.1038/s41418-025-01584-7.
Huizhi Wang 1 2,  Liuliu Wu 3 4,  Chong Liu 5,  Xueming Zhao 2,  Luhao Cui 2,  Jianing Gao 2,  Chaonan Zhang 1 2,  Tingting Du 2,  Lin Shi 1,  Yuchen Ji 6,  Yilei Xiao 7,  Jianguo Zhang 8 9,  Wenjun Tu 10,  Fangang Meng 11 12 13 14,  Chunlei Han 15 16
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 2 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
  • 3 Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China.
  • 4 Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing, China.
  • 5 Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
  • 6 Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 7 Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong, China. yileixiao@163.com.
  • 8 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. jianguozhang@ccmu.edu.cn.
  • 9 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. jianguozhang@ccmu.edu.cn.
  • 10 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. tuwenjun@irm-cams.ac.cn.
  • 11 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. fgmeng@ccmu.edu.cn.
  • 12 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. fgmeng@ccmu.edu.cn.
  • 13 Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. fgmeng@ccmu.edu.cn.
  • 14 Chinese Institute for Brain Research, Beijing, China. fgmeng@ccmu.edu.cn.
  • 15 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. hanchunlei622@163.com.
  • 16 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. hanchunlei622@163.com.
PMID: 40983632 DOI: 10.1038/s41418-025-01584-7
Abstract

Pyroptosis is strongly associated with refractory epilepsy. However, the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various neurological disorder processes by regulating programmed cell death. In this study, we identified a novel lncRNA, lncMCL1, by high-throughput screening, which suppresses NLRP3 inflammasome-dependent neural Pyroptosis in epilepsy. We demonstrated that lncMCL1 is aberrantly underexpressed in the hippocampus and cortex of epilepsy patients, a phenomenon that was validated in various mouse and rat epilepsy models. Through CRISPR/Cas9, siRNA, and viral manipulation, gain- and loss-of-function experiments confirmed that lncMCL1 inhibits neuronal Pyroptosis in vivo and in vitro and exerts antiepileptic effects. Mechanistically, lncMCL1 acts as a scaffold to modulate DDX3X protein stabilization by enhancing NEDD4-mediated DDX3X K48 ubiquitination, thereby inhibiting neural Pyroptosis through the suppression of NLRP3 inflammasome signalling. Additionally, IL-18/IL-1β, downstream cytokines of Pyroptosis, inhibit lncMCL1 expression through the activation of a shared pathway, the STAT3 pathway, forming a feedback loop. Our findings identify lncMCL1 as a critical regulator of neural cell Pyroptosis and a promising therapeutic target for refractory epilepsy.

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