miR-146a-5p mitigates ethanol-induced neuroinflammation by targeting Btg2-dependent microglial activation.

Background: Chronic alcohol exposure leads to progressive neurodegeneration, primarily driven by sustained neuroinflammation and microglial activation. While microRNAs are key regulators of neuroimmune responses, the specific role of miR-146a-5p and its downstream targets in ethyl alcohol (EtOH)-induced neuroinflammatory injury remain poorly understood. Methods: A chronic EtOH exposure model was established in C57BL/6 mice and BV-2 microglial cells. Neuroinflammatory damage was assessed using behavioral tests (Morris water maze), apoptosis assays, cytokine quantification, and immunostaining. The regulatory relationship between miR-146a-5p and its target gene Btg2 was investigated using luciferase reporter and RNA pull-down assays, combined with gain-of-function approaches. Results: EtOH exposure significantly downregulated miR-146a-5p expression in both mouse hippocampal tissue and BV-2 cells. Overexpression of miR-146a-5p in vivo improved spatial learning and memory, reduced neuronal apoptosis, and attenuated microglial activation and pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) production. Mechanistically, Btg2 was identified as a direct target of miR-146a-5p. EtOH-induced Btg2 upregulation was reversed by miR-146a-5p overexpression in vitro. Importantly, restoring Btg2 expression abolished the anti-inflammatory and anti-apoptotic effects of miR-146a-5p in EtOH-treated BV-2 cells. Conclusion: This study identifies the miR-146a-5p/Btg2 axis as a critical regulator of EtOH-induced microglial activation and neuroinflammation. Targeting this pathway may offer a promising therapeutic strategy for alcohol-related neurodegeneration.