USP25 UPREGULATION BOOSTS GSDMD -MEDIATED PYROPTOSIS OF ACINAR CELLS IN ACUTE PANCREATITIS.

Acute pancreatitis (AP) is an inflammation-associated disorder in the digestive system. Ubiquitin-specific peptidase 25 ( USP25 ) can modulate inflammation in diseases. This study expounded on the role of USP25 in pyroptosis of acinar cells in AP. Acinar cells were treated with lipopolysaccharide (LPS) and caerulein (CRE) to induce AP. Afterward, the expression patterns of USP25 , microRNA (miR)-10a-5p, and Krüppel-like factor 4 ( KLF4 ) in acinar cells were examined. Then, acinar cell viability and levels of NLR family pyrin-domain containing 3 (NLRP3), cleaved caspase-1, cleaved N -terminal gasdermin D ( GSDMD - N ), interleukin (IL)-1β, and IL-18 were determined. We observed that USP25 was highly expressed in AP models, and silencing USP25 increased cell viability and inhibited pyroptosis of AP acinar cells. The bindings of USP25 to KLF4 and miR-10a-5p to KLF4 and the GSDMD 3'UTR sequence were validated. We found that USP25 binding to KLF4 inhibited ubiquitination degradation of KLF4 , KLF4 transcriptionally decreased miR-10a-5p expression, and miR-10a-5p targeted GSDMD expression. Finally, rescue experiments proved that KLF4 overexpression or miR-10a-5p suppression enhanced pyroptosis of AP acinar cells. Overall, USP25 stabilized KLF4 expression through deubiquitination, limited miR-10a-5p expression, and increased GSDMD expression, finally promoting pyroptosis of acinar cells in AP.