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

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.