Epigenetic regulation of INPP5D and its downstream molecular network in autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is a representative manifestation of IgG4-related disease characterized by lymphoplasmacytic inflammation and storiform fibrosis. Although epigenetic dysregulation has been implicated in autoimmune diseases, its contribution to the pathogenesis of AIP remains unclear. Genome-wide DNA methylation profiling was performed using the Infinium MethylationEPIC array in tissues affected by AIP and obstructive pancreatitis (OP). Differentially methylated regions (DMRs) were identified and subjected to pathway enrichment analysis. Among the significantly enriched gene sets, GNF2_INPP5D showed the strongest enrichment and was selected for further investigation. INPP5D promoter methylation was analyzed, and its protein expression was evaluated by immunohistochemistry. Single-cell RNA sequencing (scRNA-seq) was performed to identify the cells expressing INPP5D . Pathway enrichment analysis showed significant enrichment of the INPP5D-associated immune-regulatory network in AIP. Promoter-associated CpG probes within the INPP5D locus showed predominant hypomethylation in AIP compared with the findings in OP (adjusted p < 0.05). In contrast, immunohistochemistry demonstrated reduced INPP5D expression in spindle-shaped stromal macrophage/histiocyte-lineage cells in AIP tissues. scRNA-seq analysis identified INPP5D expression predominantly in C1QC-positive macrophages and lymphocytes. AIP is characterized by epigenetic remodeling of the INPP5D-associated immune-regulatory network accompanied by reduced INPP5D expression in stromal macrophage-lineage cells. These findings provide evidence for an association between altered INPP5D-related epigenetic regulation and the characteristic fibro-inflammatory microenvironment of AIP. INPP5D may represent a candidate biomarker and a potential therapeutic target in IgG4-related disease.