Alanine-
serine-
cysteine transporter 2 (ASCT2) is reported to participate in the progression of
tumors and
metabolic diseases. It is also considered to play a crucial role in the
glutamate-
glutamine shuttle of neuroglial network. However, it remains unclear the involvement of ASCT2 in neurological diseases such as
Parkinson's disease (PD). In this study, we demonstrated that high expression of ASCT2 in the plasma samples of PD patients and the midbrain of
MPTP mouse models is positively correlated with
dyskinesia. We further illustrated that ASCT2 expressed in astrocytes rather than neurons significantly upregulated in response to either MPP+ or LPS/
ATP challenge. Genetic ablation of astrocytic ASCT2 alleviated the
neuroinflammation and rescued dopaminergic (DA) neuron damage in PD models in vitro and in vivo. Notably, the binding of ASCT2 to NLRP3 aggravates astrocytic
inflammasome-triggered
neuroinflammation. Then a panel of 2513 FDA-approved drugs were performed via virtual molecular screening based on the target ASCT2 and we succeed in getting the
drug talniflumate. It is validated
talniflumate impedes astrocytic
inflammation and prevents degeneration of DA neurons in PD models. Collectively, these findings reveal the role of astrocytic ASCT2 in the pathogenesis of PD, broaden the therapeutic strategy and provide a promising candidate
drug for PD treatment.