Tweak regulates glial cell activation in temporal lobe epilepsy through a positive feedback circuit

Gliosis is a hallmark of temporal lobe epilepsy (TLE) and contributes to disease progression and cognitive deficits, yet its regulatory mechanisms remain poorly understood. Tweak (tumor necrosis factor-related weak inducer of apoptosis) has been implicated in glial activation and inflammation, but its role in TLE remains unclear. In this study, a TLE mouse model was established by intraperitoneal injection of pilocarpine. Knockdown of either Tweak or long non-coding RNA Snhg3 (small nucleolar RNA host gene 3), a lncRNA co-expressed with Tweak, alleviated glial activation, neuroinflammatory, and cognitive behavioral deficits in TLE mice. Conversely, up-regulation of Tweak or Snhg3 promoted proliferation, migration, and inflammatory factor secretion in mouse astrocytes (MAs), indicating that TWEAK and Snhg3 each induce glial activation in vitro. Mechanistically, Tweak/Fn14 and Stat1 signaling reciprocally promoted each other, with Stat1 directly binding to the Snhg3 promoter to enhance its transcription, while Tweak and Snhg3 mutually upregulated each other and synergistically activated the Stat1 pathway, forming a positive feedback loop in MAs that collectively drived astrocyte activation. In conclusion, this study identifies a positive feedback regulation loop involving Tweak/Stat1/Snhg3 that contributes to glial cell activation in TLE mice. These findings highlight Tweak and Snhg3 as potential therapeutic targets for gliosis-related cognitive impairment in epilepsy.