Dysregulation of the SARA-Smurf2 axis in Temporal Lobe Epilepsy and its modulation by Losartan

Temporal lobe epilepsy (TLE) is a focal epilepsy characterized by recurrent seizures and frequent pharmacoresistance. Increasing evidence suggests that dysregulation of transforming growth factor β (TGFβ) signaling contributes to epileptogenesis and neuroinflammation. SARA (Smad Anchor for Receptor Activation) is an adaptor protein that facilitates Smad2/3 phosphorylation and TGFβ signaling, whereas Smurf2, an E3 ubiquitin ligase, contributes to the degradation of SARA and TGFβ receptors. However, the role of the SARA-Smurf2 axis in regulating TGFβ signaling during TLE has not been described, and whether this pathway can be therapeutically targeted remains unknown. Using a pilocarpine-induced status epilepticus (SE) model and astrocytes derived from patients with refractory TLE, we identified disruption of the SARA-Smurf2 axis in both systems. SARA and GFAP levels were increased, whereas Smurf2 showed an inadequate increase in SE and was reduced in TLE astrocytes. Treatment of SE and TLE models with Losartan, an angiotensin II type 1 receptor antagonist, shifted SARA and Smurf2 levels toward control values and reduced seizure frequency and duration in SE model. Together, these findings identify dysregulation of the SARA-Smurf2 axis as a molecular feature of TLE and support SARA as a potential therapeutic target. Finally, our results provide experimental evidence supporting the repurposing of Losartan as a potential treatment strategy for drug-resistant epilepsy.