ABSTRACT Objectives Metabolic dysfunction‐associated steatohepatitis (MASH) is a significant risk factor for cirrhosis and hepatocellular carcinoma, for which there is currently no effective treatment. This study aimed to investigate the regulatory mechanism between endoplasmic reticulum stress (ER stress) and pyroptosis in the liver under the context of MASH. Methods and Results Pyroptosis was examined in both in vivo and in vitro ER stress models. The expression levels of nucleotide‐binding oligomerisation domain‐like receptor protein 3 (NLRP3), gasdermin D (GSDMD), caspase‐1, IL‐1β, and IL‐18 tended to increase, and “ASC specks” colocalised with the swollen ER in living cells. However, in the pyroptotic model, increased ER stress was not observed. Moreover, the overexpression of inositol‐requiring enzyme 1α (IRE‐1α), one of the main ER stress sensors, led to increases in the levels of NLRP3 and GSDMD. However, after IRE‐1α was blocked by chemical inhibitors or siRNAs, pyroptosis was also abrogated. These data showed that ER stress regulated pyroptosis through IRE‐1α. Furthermore, the immunoprecipitation results clearly indicated that GSDMD efficiently bound to IRE‐1α when ER stress was stimulated. In the MASH model, IRE‐1α was specifically inhibited by pharmacological or genetic methods, which improved the pathology of MASH by alleviating ER stress and pyroptosis. In patients with MASH, both ER stress markers and pyroptosis markers including IRE‐1α, glucose‐regulated protein 78, GSDMD/GSDMD‐N, p20, and NLRP3, are highly expressed in the liver. Conclusions This study revealed that ER stress may regulate pyroptosis through IRE‐1α‐GSDMD pathway, which accelerates the progression of MASH. These findings may offer new insights for the treatment of MASH.

Inhibition of IRE‐1α Alleviates Pyroptosis and Metabolic Dysfunction‐Associated Steatohepatitis by Suppressing Gasdermin D