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However, the molecular mechanisms driving \u03b2 cell death during ER stress remain insufficiently defined, limiting development of protective therapies. GRP78, an ER chaperone, is the master regulator of unfolded protein response (UPR), suppressing UPR initiators during the unstressed state and releasing them to allow UPR activation during stress. To dissect the pathways leading to ER-stress response related \u03b2 cell decompensation, we engineered mice genetically lacking GRP78 in pancreatic \u03b2 cells. GRP78 deletion caused acute insulin-deficient diabetes in pups before weaning, with reduced \u03b2 cell mass due to increased apoptosis. Molecular studies identified deregulated UPR, specifically IRE1 activity, as driving cell death. Unbiased and targeted analyses identified a JNK-p53 axis downstream of IRE1 kinase as a key mediator of \u03b2 cell death during UPR activation. In vivo JNK inhibition protected against \u03b2 cell death in 2 distinct ER stress diabetes models. In human \u03b2 cells, pharmacological inhibition of both JNK and p53 improved \u03b2 cell survival during GRP78 knockdown\u2013induced UPR. These findings provide insight into mechanisms causing \u03b2 cell death during ER stress and outline possible therapeutic targets to preserve insulin secretory capacity in diabetes.<\/jats:p>\n                  <jats:p\/>\n                  <jats:p>This study identifies JNK and p53 as mediators of pancreatic beta cell death during ER stress, which could lead beta cell preserving therapies for diabetes.<\/jats:p>","DOI":"10.1172\/jci193035","type":"journal-article","created":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T19:50:23Z","timestamp":1785700223000},"source":"Crossref","is-referenced-by-count":2,"title":["JNK and p53 cause human and mouse \u03b2 cell death during excessive unfolded protein response"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1435-7612","authenticated-orcid":true,"given":"Rohit B.","family":"Sharma","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism and the Joan and Sanford I. 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