Interleukin-1 receptor associated kinase 3 (IRAK3) is a cytoplasmic homeostatic mediator of inflammatory responses. It inhibits signalling cascades downstream of myddosome complexes related to toll-like receptors. IRAK3 contains a death domain, a pseudokinase domain with a guanylate cyclase centre, and a C-terminus domain associated with tumour necrosis factor receptor associated factor 6 (TRAF6) [1]. It is involved in the MyD88-TRAF6 pathway and is a key modulator in the human inflammatory pathway, also associated with endotoxin tolerance and sepsis [1,2,3,5,6].

In acute pancreatitis, Irak3-/-mice showed enhanced migration of CCR2 + monocytes into the pancreas and a pro-inflammatory type 1 immune response. In a mild model, this led to decreased pancreatic damage, while in a severe model, it drove a severe systemic inflammatory response syndrome (SIRS) and increased local and systemic damage. This indicates that IRAK3-mediated suppression of pro-inflammatory MyD88/IRAK signaling affects disease severity [4].

In breast cancer, silencing of circular RNA circ_IRAK3 induced apoptosis, curbed cell proliferation, migration, and invasion, and decreased tumor growth in vivo. circ_IRAK3 promoted breast cancer progression by modulating the miR-603/KIF2A axis [7].

In rheumatoid arthritis, CD14 + monocytes from patients with high disease activity had lower levels of IRAK3 expression compared to those with low/moderate activity [8].

In conclusion, IRAK3 is a crucial modulator of inflammatory responses. Its function is revealed through gene-knockout models in various disease conditions such as acute pancreatitis, breast cancer, and rheumatoid arthritis. These models help understand its role in disease development, providing potential targets for treatment.