Abstract: The innate immune system of the central nervous system (CNS), long viewed as primarily microgliadriven, is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling. Chronic alcohol exposure triggers oxidative stress, glial activation, and sustained inflammation, ultimately contributing to cognitive decline and neuronal injury. While microglial inflammasomes, particularly nucleotide-binding domain, leucinerich–containing family, pyrin domain–containing-3 (NLRP3), have garnered attention in alcohol-related neuroinflammation, the recent study by Singh et al. (2025) extends this paradigm by identifying a miR-339-regulated NLRP6 inflammasome response in human fetal astrocytes exposed to ethanol. Their findings shed light on a potential astrocytespecific inflammatory mechanism, but also raise key questions about its translational applicability (Figure 1). Specifically, the use of proliferating fetal astrocytes as a model system may better reflect mechanisms relevant to fetal alcohol spectrum disorders than adult alcohol use disorder (AUD). Furthermore, the focus on a single inflammasome axis overlooks the complex interplay among multiple innate immune sensors and their divergent roles across CNS cell types and species. In this Perspective, we critically examine the implications of the miR-339/NLRP6 axis in the broader landscape of astrocytic inflammasome research, discuss the limitations of the current model system, and highlight future directions for establishing NLRP6 as a viable therapeutic target for alcohol-induced neuroinflammation.