Macrophage TRIM21 Inhibition Ameliorates Murine Acute Pancreatitis via PHB2‐Mediated Mitochondrial Stabilization

Acute pancreatitis (AP) involves acinar cell death and severe inflammation. 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-dependent 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-localization with macrophages. Macrophage-specific Trim21 ablation mitigates pancreatic damage and systemic inflammation. Conversely, TRIM21 activation aggravates disease severity. Mechanistically, TRIM21 promotes K11-linked ubiquitination and proteasomal degradation of PHB2, leading to mtDNA accumulation in the cytosol via impaired PHB2-mediated mitophagy. Dysregulation of mtDNA homeostasis activates the cGAS-STING 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-associated inflammation, providing a potential therapeutic strategy for inflammatory pancreatic diseases.