Primetime for the Gasdermins Seesaw in Intestinal Homeostasis and Digestive Disorders

ABSTRACT The five pore‐forming gasdermins (GSDMs, namely GSDMA‐E) are best known for executing pyroptosis, a lytic and highly inflammatory form of programmed cell death. Accumulating evidence over the past decade has unveiled diverse nonlytic functions of GSDMs in digestive homeostasis and disease. GSDMs preserve intestinal barrier integrity and mucosal immunity under physiological conditions, whereas their dysregulated activation fuels tissue injury across a spectrum of digestive diseases, including inflammatory bowel disease, acute intestinal injury, radiation enteritis, acute pancreatitis, and liver disorders. Notably, the functional outcome of GSDM activation is highly context‐dependent: the same protein can be either protective or injurious. This duality extends to digestive oncology, where GSDM‐mediated pyroptosis can stimulate or suppress antitumor immunity. GSDM‐targeted drugs, including GSDMD agonists, GSDMD inhibitors, and GSDME inhibitors, have shown encouraging efficacy in preclinical models, although none have yet reached the clinic. Here, we review the dual roles of GSDMs across the digestive system, outline the mechanistic basis of their form‐, cell‐, and tissue‐specific functions, and discuss the progress and remaining challenges in GSDM‐targeted therapy.