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Although the E3 ubiquitin ligase TRIM21 regulates inflammation, its role in the pathogenesis of AP remains undefined. This study aims to explore the role of TRIM21 in regulating inflammation during AP. In this study, TRIM21 levels show a severity\u2010dependent increase in patients with AP, which is more than that in healthy controls. Consistently, increased TRIM21 expression is observed in the murine models of AP and exhibits spatial co\u2010localization with macrophages. Macrophage\u2010specific\n                    <jats:italic>Trim21<\/jats:italic>\n                    ablation mitigates pancreatic damage and systemic inflammation. Conversely, TRIM21 activation aggravates disease severity. Mechanistically, TRIM21 promotes K11\u2010linked ubiquitination and proteasomal degradation of PHB2, leading to mtDNA accumulation in the cytosol via impaired PHB2\u2010mediated mitophagy. Dysregulation of mtDNA homeostasis activates the cGAS\u2010STING axis, thereby intensifying inflammation during AP progression. Additionally, pharmacological inhibition of TRIM21 with quisinostat mitigates AP progression. Our findings reveal the critical role of TRIM21 in AP\u2010associated inflammation, providing a potential therapeutic strategy for inflammatory pancreatic diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517877","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T04:51:16Z","timestamp":1769143876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage TRIM21 Inhibition Ameliorates Murine Acute Pancreatitis via PHB2\u2010Mediated Mitochondrial Stabilization"],"prefix":"10.1002","volume":"13","author":[{"given":"Yansong","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine Qilu Hospital of Shandong University  Jinan China"},{"name":"Shandong Provincial Clinical Research Center For Emergency and Critical Care Medicine Chest Pain Center Institute of Emergency and Critical Care Medicine of Shandong University Qilu Hospital of Shandong University  Jinan China"},{"name":"Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine Key Laboratory of Emergency and Critical Care Medicine of Shandong Province China's Ministry of Education Key Laboratory of Cardiopulmonary\u2010Cerebral Resuscitation Research of Shandong Province Qilu Hospital of Shandong University  Jinan China"},{"name":"NMPA Key Laboratory For Clinical Research and Evaluation of Innovative Drug Qilu Hospital of Shandong University  Jinan China"},{"name":"National Key Laboratory For Innovation and Transformation of Luobing Theory The Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education Chinese National Health Commission and Chinese Academy of Medical Sciences Qilu Hospital of Shandong University  Jinan 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