Taurine Attenuates Neuronal Ferroptosis by CSF-Derived Exosomes of GABABR Encephalitis Through GABABR/NF2/P-YAP Pathway.

GABAB receptor (GABABR) encephalitis represents a rare subtype of paraneoplastic limbic encephalitis (LE), characterized by persistent seizures and cognitive impairments. Nevertheless, the precise phenotype and underlying mechanisms of neuronal dysfunction associated with intrathecal lymphocytes in GABABR encephalitis remain inadequately understood. In the present study, we demonstrate that exosomes derived from the cerebrospinal fluid (CSF) of patients with GABABR encephalitis can induce neuronal ferroptosis, oxidative stress, iron accumulation, and lipid hyperoxidation in an in vitro model of anti-GABABR encephalitis. MicroRNA (miRNA) sequencing revealed that miR-92a-3p is a differentially expressed miRNA in CSF exosomes, and its expression was positively correlated with unfavorable clinical outcomes in GABABR encephalitis patients during a 6-month follow-up period. The NF2/P-YAP signaling pathway was identified as a downstream effector of miR-92a-3p, influencing the expression of ACSL4/GPX4 and IL-6, with the expression of these genes being enhanced following taurine supplementation. Clinically, taurine levels in CSF exhibited a negative correlation with IL-6 levels, CSF cell counts, blood-CSF barrier integrity, and clinical prognosis in GABABR encephalitis. Mechanistically, taurine effectively reduced reactive oxygen species (ROS) and iron accumulation, as well as IL-6 production, while modulating the levels of NF2, P-YAP, ACSL4, and GPX4 in neurons treated with CSF-derived exosomes from GABABR encephalitis through GABABR activation. Proliferation assays indicated that extracellular taurine intake activated CD4 + T cells, CD8 + T cells, and CD19 + B cells in the CSF of patients with GABABR encephalitis. In summary, our findings reveal for the first time that intrathecal lymphocytes in GABABR encephalitis maintain an activated state by absorbing extracellular taurine and that decreased taurine levels in CSF promote neuronal ferroptosis via the miR-92a-3p-mediated NF2/P-YAP/ACSL4 pathway.