Multiple sclerosis (MS) and Neuromyelitis Optica (NMO) are immune-related CNS inflammatory diseases that often present with overlapping clinical symptoms, leading to frequent misdiagnosis, particularly in aquaporin-4 seronegative NMO patients. Identifying the underlying mechanisms of these diseases is critical for discovering biomarkers that enable timely diagnosis and effective treatment. This study included 252 participants, divided into four groups. Group I (Relapsing-Remitting MS: RRMS group), Group II (Secondary Progressive MS: SPMS group), Group III (NMO group), and Group IV (Healthy controls). Blood samples were collected from all participants to measure the expression levels of Neuregulin-1 (NRG1), lncRNA Ftx, and miR-382-5p. The results showed that NRG1 levels were significantly lower in the RRMS, SPMS, NMO groups compared to healthy controls, with the most pronounced reduction observed in NMO, suggesting NRG1 may serve as a potential biomarker for differentiating NMO from MS, especially in cases where traditional diagnostic criteria are inconclusive. lncRNA Ftx, a sponge for miR-382-5p, exhibited an opposite trend to miR-382-5p and was significantly downregulated in NMO compared to MS, SPMS, RRMS, and healthy controls, suggesting its potential as a promising biomarker. Our findings highlight the potential of NRG1, lncRNA Ftx, and miR-382-5p expression as diagnostic, screening, and prognostic biomarkers, as well as tools for the differential diagnosis of NMO and MS.