Exercise-Mediated Regulation of Pyroptosis in Diabetes and Its Complications: Molecular Mechanisms and Translational Perspectives

Diabetes mellitus (DM) is characterized by chronic metabolic stress and low-grade inflammation that progressively damage multiple organs. Pyroptosis, a gasdermin-mediated form of inflammatory regulated cell death, may connect hyperglycemia, lipotoxicity, oxidative stress, mitochondrial dysfunction, and inflammasome activation to tissue injury. This review synthesizes evidence for pyroptosis in pancreatic β cells, adipose tissue, the liver, heart, kidneys, skeletal muscle, bone, retina, nervous system, and lungs, and critically evaluates how exercise may modulate these processes. Exercise improves metabolic and mitochondrial homeostasis; reduces reactive oxygen species, oxidized mitochondrial DNA, and extracellular adenosine triphosphate; and regulates thioredoxin-interacting protein/NLRP3, P2X/pannexin 1, and cyclic GMP-AMP synthase-stimulator of interferon genes signaling. Exercise-induced factors, including irisin, meteorin-like protein, and adropin, may further mediate cross-organ communication. The most direct antipyroptotic evidence currently concerns diabetic cardiomyopathy, muscle atrophy, and osteoporosis, whereas studies of adipose tissue, metabolic dysfunction-associated steatotic liver disease, and diabetic kidney disease often demonstrate inflammasome suppression without establishing gasdermin-dependent membrane lysis. Clinical benefits therefore cannot yet be attributed directly to pyroptosis inhibition. Standardized exercise protocols, cell-specific models, complete pyroptosis evidence chains, and clinically applicable biomarkers are required to translate these mechanisms into precision exercise prescriptions.