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Cellular stress–mediated chaperones are linked to liver macrophage activation and inflammation in alcohol‐associated liver disease (ALD). In this study, we investigate the role of endoplasmic reticulum (ER) resident stress chaperone GP96/HSP90B1/GRP94, paralog of the HSP90 family, in ALD pathogenesis. We hypothesize that ER resident chaperone, heat shock protein GP96, plays a crucial role in alcohol‐associated liver inflammation and contributes to liver injury. We show high expression of GP96/HSP90B1 and GRP78/HSPA5 in human alcohol‐associated hepatitis livers as well as in mouse ALD livers with induction of GP96 prominent in alcohol‐exposed macrophages. Myeloid‐specific GP96 deficient (M‐GP96KO) mice failed to induce alcohol‐associated liver injury. Alcohol‐fed M‐GP96KO mice exhibit significant reduction in steatosis, serum endotoxin, and pro‐inflammatory cytokines compared with wild‐type mice. Anti‐inflammatory cytokines interleukin‐10 and transforming growth factor β, as well as activating transcription factor 3 and triggering receptor expressed on myeloid cells 2, markers of restorative macrophages, were higher in alcohol‐fed M‐GP96KO livers. M‐GP96KO mice exhibit protection in a model of endotoxin‐mediated liver injury  in vivo , which is in agreement with reduced inflammatory responses during  ex vivo  lipopolysaccharide/endotoxin– stimulated bone marrow–derived macrophages from M‐GP96KO mice. Furthermore, we show that liver macrophages from alcohol‐fed M‐GP96KO mice show compensatory induction of GRP78 messenger RNA, likely due to increased splicing of X‐box binding protein‐1. Finally, we show that inhibition of GP96 using a specific pharmacological agent, PU‐WS13 or small interfering RNA, alleviates inflammatory responses in primary macrophages.  Conclusion:  Myeloid ER resident GP96 promotes alcohol‐induced liver damage through activation of liver macrophage inflammatory responses, alteration in lipid homeostasis, and ER stress. These findings highlight a critical role for liver macrophage ER resident chaperone GP96/HSP90B1 in ALD, and its targeted inhibition represents a promising therapeutic approach in ALD.

Myeloid Endoplasmic Reticulum Resident Chaperone GP96 Facilitates Inflammation and Steatosis in Alcohol‐Associated Liver Disease