{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:48:02Z","timestamp":1791398882395,"version":"4.3.3"},"reference-count":30,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["(Chengdu, China, 82170590, 81870609, and 82170075)"],"award-info":[{"award-number":["(Chengdu, China, 82170590, 81870609, and 82170075)"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Metabolic dysfunction\u2010associated 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>Pyroptosis was examined in both in\u00a0vivo and in\u00a0vitro ER stress models. The expression levels of nucleotide\u2010binding oligomerisation domain\u2010like receptor protein 3 (NLRP3), gasdermin D (GSDMD), caspase\u20101, IL\u20101\u03b2, and IL\u201018 tended to increase, and \u201cASC specks\u201d colocalised with the swollen ER in living cells. However, in the pyroptotic model, increased ER stress was not observed. Moreover, the overexpression of inositol\u2010requiring enzyme 1\u03b1 (IRE\u20101\u03b1), one of the main ER stress sensors, led to increases in the levels of NLRP3 and GSDMD. However, after IRE\u20101\u03b1 was blocked by chemical inhibitors or siRNAs, pyroptosis was also abrogated. These data showed that ER stress regulated pyroptosis through IRE\u20101\u03b1. Furthermore, the immunoprecipitation results clearly indicated that GSDMD efficiently bound to IRE\u20101\u03b1 when ER stress was stimulated. In the MASH model, IRE\u20101\u03b1 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\u20101\u03b1, glucose\u2010regulated protein 78, GSDMD\/GSDMD\u2010N, p20, and NLRP3, are highly expressed in the liver.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study revealed that ER stress may regulate pyroptosis through IRE\u20101\u03b1\u2010GSDMD pathway, which accelerates the progression of MASH. These findings may offer new insights for the treatment of MASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.16234","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T07:43:42Z","timestamp":1736235822000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of\n                    <scp>IRE<\/scp>\n                    \u20101\u03b1 Alleviates Pyroptosis and Metabolic Dysfunction\u2010Associated Steatohepatitis by Suppressing Gasdermin D"],"prefix":"10.1111","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7856-6923","authenticated-orcid":false,"given":"Xin","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Liver Transplantation Center and National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology West China Hospital, Sichuan University  Chengdu 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