GSDME deficiency enhances neutrophil recruitment and exacerbates irinotecan-induced intestinal mucositis

Abstract Intestinal mucositis is a clinically significant adverse event of cancer chemotherapy, particularly in regimens containing irinotecan. Gasdermin E (GSDME) is a pore-forming protein that functions as a molecular switch between apoptosis and pyroptosis and has been implicated in the pathogenesis of various diseases. In the present study, we generated Gsdme -deficient mice and investigated the role of GSDME in chemotherapy-induced intestinal mucositis. Within the gastrointestinal tract, GSDME was highly expressed from the distal jejunum to the ileum. Under steady-state conditions, GSDME had no effect on mucosal morphology or gut microbiota composition. Irinotecan treatment caused a modest intestinal shortening and histological injury, which were further exacerbated in Gsdme -deficient mice. GSDME deficiency also enhanced the upregulation of neutrophil-attracting chemokines ( Cxcl1 and Cxcl2 ) and promoted neutrophil infiltration in the crypt regions. Furthermore, GSDME deficiency resulted in increased DNA fragmentation and reduced expression of occludin, a tight junction protein, while myeloperoxidase (MPO) expression was markedly increased in the crypts. Mechanistically, the isolated GSDME-deficient neutrophils showed prolonged lifespan, while wild-type neutrophils rapidly underwent pyroptosis. Notably, neutrophil depletion or treatment with a serine protease inhibitor rescued the shortening of the small intestine, histological intestinal injury, and diarrhea in Gsdme -deficient mice. Moreover, the correlation between GSDME expression and neutrophil-associated gene sets was confirmed in human intestinal inflammation. Collectively, these findings demonstrate that GSDME deficiency enhances neutrophil recruitment and activation in the crypts, thereby exacerbating irinotecan-induced mucositis. GSDME plays a protective role in the intestinal mucosa and represents a potential therapeutic target for chemotherapy-induced intestinal mucositis.