miR-6836-5p Drives Astrocyte Pro-survival Signaling Through DLG2-Hippo-YAP Pathway Under AQP4-IgG + ve NMOSD Stress

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy mainly driven by serum antibodies against aquaporin-4 (AQP4-IgG). While antibody-mediated injury to astrocytes is well documented, the intrinsic cellular responses that influence astrocyte survival under such stress remain poorly understood. In this study, differentiated U87MG astrocytoma cells served as an in vitro model to examine the effects of AQP4-IgG + ve NMOSD patient sera on microRNA-mediated signaling. Small RNA sequencing and qRT-PCR revealed that hsa-miR-6836-5p was the most strongly induced miRNA within 4 h of exposure, consistent with the peak downregulation of AQP4. Functional enrichment and target prediction identified the Hippo-YAP signaling pathway, with Discs Large Homolog 2 (DLG2) as a key downstream target. AQP4-IgG + ve sera reduced DLG2 expression, decreased LATS1 and YAP phosphorylation, and upregulated YAP-dependent pro-survival genes (CTGF, CYR61, GLI2), along with an increased BCL-2/BAX ratio, initiating an acute pro-survival response. Inhibition of miR-6836-5p restored DLG2 levels, reactivated the Hippo signaling pathway, and reinstated apoptotic signaling. These findings unveil a novel miR-6836-5p-DLG2-Hippo-YAP axis that promotes pro-survival signaling in astrocytes under autoimmune stress, indicating miR-6836-5p as a potential molecular regulator of astrocyte fate in NMOSD.