HBO1-mediated epigenetic regulation of LAMB1 in pancreatic ductal injury during acute pancreatitis

Acute pancreatitis (AP) is an inflammatory disorder characterized by abnormal activation of pancreatic enzymes, leading to autodigestion, necrosis, and systemic inflammation. Despite improvements in fluid resuscitation, nutritional support, and minimally invasive interventions, there remains a lack of effective targeted therapies due to limited understanding of its molecular mechanisms. Increasing evidence suggests that pancreatic ductal epithelial cells (PDECs), the primary structural component of the exocrine ductal system, play a critical role in early barrier dysfunction and amplification of inflammation during AP.

Pancreatic juice samples were collected from AP patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). An in vitro pancreatic juice-stimulated model was established using human pancreatic ductal epithelial cells (HPNE). Transcriptomic profiling was performed to identify differentially expressed genes, followed by functional validation through molecular and animal experiments. Western blotting, immunofluorescence, flow cytometry, and mRFP-GFP-LC3 assays were used to assess apoptosis and autophagy. Cerulein-induced rat models of AP were utilized to verify in vivo findings.

Transcriptome analysis revealed significant enrichment of the extracellular matrix (ECM)–receptor interaction pathway, with Laminin subunit beta 1 (LAMB1) markedly downregulated in pancreatic juice-treated PDECs. Suppression of LAMB1 was associated with reduced cell viability, excessive autophagy, and increased apoptosis, while LAMB1 overexpression alleviated these effects and restored epithelial function. Furthermore, the histone acetyltransferase HBO1 (KAT7) was found to be downregulated following pancreatic juice exposure, accompanied by decreased histone acetylation at H3K14ac, H3K18ac, H3K27ac, H4K5ac, H4K8ac, and H4K12ac sites. Overexpression of HBO1 restored LAMB1 expression in pancreatic juice-stimulated cells, suggesting a potential association between HBO1-related histone acetylation changes and LAMB1 expression. CUT&RUN-qPCR further showed that HBO1 was enriched at the LAMB1 promoter, and this enrichment was reduced by pancreatic juice stimulation but partially restored by HBO1 overexpression.

LAMB1 may play a protective role in pancreatic ductal epithelial injury during acute pancreatitis. Pancreatic juice stimulation was associated with downregulation of LAMB1 and HBO1, together with enhanced apoptosis and excessive autophagy, whereas restoration of LAMB1 expression attenuated these injury-related changes. These findings support a promoter-associated HBO1–LAMB1 epigenetic regulatory mechanism in pancreatic ductal injury during acute pancreatitis.