Background <p>Dysregulation of neutrophil extracellular traps (NETs), through overproduction or poor clearance, can lead to tissue damage and is linked to inflammatory conditions like type 2 diabetes mellitus (T2DM). Irisin, a hormone believed to modulate energy metabolism and enhance insulin sensitivity, holds promise as a potential treatment for T2DM. This study aims to investigate the role of Irisin in alleviating β-cell pyroptosis by inhibiting NETs formation and elucidating the underlying molecular mechanisms.</p> Methods <p>C57BL/6J mice were used to establish T2DM through a high-fat diet and streptozotocin injection. Glucose metabolism was evaluated using oral glucose tolerance tests and fasting plasma insulin measurements. Histological analysis of pancreatic tissue was carried out using hematoxylin and eosin staining, while the formation of NETs was assessed through immunofluorescent staining. In vitro, Min6 cells were cultured under high-glucose conditions to simulate T2DM, and treated with Irisin. Irisin’s impact on NETs was determined using Sytox Green staining. Key signaling molecules were examined with Western blotting.</p> Results <p>Irisin treatment improved glucose tolerance, increased insulin levels, and reduced NETs formation in T2DM mice. Histological analysis showed decreased pancreatic tissue damage. In vitro, Irisin inhibited NETs formation through the αVβ5/FAK/ERK pathway and reduced NETs-induced pyroptosis in β-cells via the STING/IRE1α/NLRP1 pathway. Blocking these pathways confirmed Irisin’s protective role against NETs-mediated pyroptosis.</p> Conclusion <p>Irisin exhibits protective effects against β-cell pyroptosis in T2DM by inhibiting NETs formation through integrin-related signaling pathways. These findings suggest that Irisin may serve as a therapeutic agent in managing T2DM by modulating NETs and preserving β-cell function.</p>