Dysregulation of the SARA–Smurf2 Regulatory Axis in Temporal Lobe Epilepsy

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ABSTRACT Temporal lobe epilepsy (TLE) is associated with dysregulation of transforming growth factor β (TGFβ) signaling, a key contributor to epileptogenesis. SARA (Smad Anchor for Receptor Activation), a central regulator of this pathway, is controlled by the E3 ubiquitin ligase Smurf2 through ubiquitination. However, the role of the SARA–Smurf2 axis in regulating TGFβ signaling during TLE has not previously 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 dysregulation of the SARA–Smurf2 pathway in both experimental systems. In SE rats, SARA and Glial Fibrillary Acidic Protein (GFAP) levels were significantly increased, whereas Smurf2 induction was insufficient to prevent SARA accumulation. In TLE-derived astrocytes, increased SARA and GFAP immunoreactivity was accompanied by reduced Smurf2 immunoreactivity and altered Smurf2 subcellular distribution. Losartan treatment restored SARA and Smurf2 immunoreactivity toward a control-like pattern in both models and reduced seizure frequency and duration in SE animals. These findings point towards a dysregulation of the SARA–Smurf2 axis as a molecular signature of TLE, support SARA as a potential therapeutic target, providing experimental evidence for the repositioning of Losartan as a potential treatment alternative for drug-resistant epilepsy, warranting further translational and clinical investigation. KEY POINTS Dysregulation of the SARA–Smurf2 axis is a molecular signature of experimental and human temporal lobe epilepsy. Impaired Smurf2-dependent regulation of SARA may sustain TGFβ signaling, astrocyte reactivity, and epileptogenesis. Losartan restores the SARA–Smurf2 axis and reduces seizures, supporting a novel therapeutic strategy for TLE.

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