IRAK1

Interleukin-1 receptor-associated kinase 1 (IRAK1) is a serine-threonine kinase that mediates signaling downstream of Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) complexes, promoting innate immune and inflammatory responses^[1][2]. Mechanistically, IRAK1 interacts with the adaptor protein MyD88 and is recruited to the myddosome, where it undergoes phosphorylation and contributes to the activation of NF-κB and MAPK pathways^[2][3]. Compared with its paralog IRAK4, IRAK1 exhibits distinct roles in hematologic malignancies, being preferentially expressed and required for maintaining viability and progenitor function in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)^[4][5]. IRAK1 also regulates cancer stemness and chemoresistance in hepatocellular carcinoma through the IRAK1/IRAK4/AP-1/AKR1B10 signaling cascade, influencing self-renewal and tumorigenicity^[6]. Alternative splicing generates the IRAK1b isoform, which is kinase-inactive but stable, adding regulatory complexity to IL-1 signaling^[7]. Pharmacologically, selective IRAK1 inhibitors, including dual IRAK1/4 compounds and covalent degraders, effectively suppress inflammatory responses, enhance chemotherapy sensitivity, and reduce leukemic or tumor-initiating cell function in preclinical models^{[8][9][10][5][11][12]}. These findings underscore the importance of IRAK1 in innate immunity, oncogenesis, and as a target for therapeutic intervention, while differentiating its function and regulation from other IRAK family members^[13][4][5].