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HIV\u20101 transactivator of transcription (Tat) and ethanol synergistically promote neuroinflammation, but the underlying molecular mechanisms remain unclear. This study aimed to determine whether endoplasmic reticulum (ER) stress regulates astrocytic NLRP6 inflammasome activation in response to HIV Tat and ethanol coexposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Mouse primary astrocytes were exposed to HIV Tat (50\u2009ng\/mL) and ethanol (50\u2009mM), individually or in combination. Astrocyte activation, NLRP6 inflammasome signaling, proinflammatory cytokine production, and ER stress responses were assessed using western blotting, immunocytochemistry, qPCR, and ELISA. ER stress was inhibited using 4\u2010phenylbutyric acid (4\u2010PBA), and NLRP6 was silenced using siRNA to define pathway hierarchy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Combined HIV Tat and ethanol exposure markedly increased astrocytic activation, NLRP6 expression, caspase\u20101 cleavage, and IL\u20101\u03b2 and IL\u201018 production compared with individual treatments. Coexposure also significantly induced ER stress markers BiP, ATF6, and phosphorylated eIF2\u03b1. Pharmacological inhibition of ER stress suppressed NLRP6 inflammasome activation and astrocytic reactivity, whereas NLRP6 knockdown attenuated inflammatory signaling without affecting ER stress markers, indicating ER stress acts upstream of NLRP6.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify an ER stress\u2013NLRP6 inflammasome axis as a potential mechanism underlying HIV Tat and ethanol\u2010induced astrocytic neuroinflammation, providing mechanistic insight into alcohol\u2010associated neuroinflammatory processes relevant to HAND.<\/jats:p>\n                  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