IRAK1, short for Interleukin-1 receptor associated kinase 1, is a pivotal signaling intermediate in interleukin-1 and Toll-like receptor-mediated signaling pathways [3]. It plays essential roles in innate immunity and inflammation, operating at the nexus of multiple inflammatory pathways [2].

In glioma, ionizing radiation induces IRAK1 expression, and its overexpression is associated with poor prognosis. IRAK1 knockdown inhibits malignancy and enhances radiosensitivity. Mechanistically, IRAK1 binds to PRDX1, preventing its ubiquitination and degradation by HECTD3, and overexpression of PRDX1 reverses the radiotherapy-sensitizing effect of IRAK1 depletion [1]. In hematologic malignancies, IRAK1, along with IRAK4, is emerging as a therapeutic target, with pre-clinical investigations suggesting it as a targetable molecular dependency [2]. In myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), cotargeting IRAK1 and IRAK4 is required to suppress leukemic stem/progenitor cell function as inhibiting IRAK4 elicits functional compensation by IRAK1 through non-canonical MyD88-independent pathways [4]. In rheumatoid arthritis, the rs1059703 T allele of IRAK1 gene increases the risk and severity of the disease in Iranian patients [5].

In conclusion, IRAK1 is crucial in innate immunity and inflammation-related signaling pathways. Its role in various diseases such as glioma, hematologic malignancies, and rheumatoid arthritis has been revealed through different research models. These findings provide potential therapeutic targets and insights into the disease mechanisms, highlighting the importance of studying IRAK1 in understanding disease processes and developing treatment strategies.

References:

1. Li, Jing, Sun, Yuchen, Zhao, Xu, Sun, Xuanzi, Zhang, Xiaozhi. 2023. Radiation induces IRAK1 expression to promote radioresistance by suppressing autophagic cell death via decreasing the ubiquitination of PRDX1 in glioma cells. In Cell death & disease, 14, 259. doi:10.1038/s41419-023-05732-0. https://pubmed.ncbi.nlm.nih.gov/37031183/

2. Bennett, Joshua, Starczynowski, Daniel T. . IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies. In Current opinion in hematology, 29, 8-19. doi:10.1097/MOH.0000000000000693. https://pubmed.ncbi.nlm.nih.gov/34743084/

3. Kim, Kyeong Min, Hwang, Na-Hee, Hyun, Ja-Shil, Shin, Dongyun. 2024. Recent Advances in IRAK1: Pharmacological and Therapeutic Aspects. In Molecules (Basel, Switzerland), 29, . doi:10.3390/molecules29102226. https://pubmed.ncbi.nlm.nih.gov/38792088/

4. Bennett, Joshua, Ishikawa, Chiharu, Agarwal, Puneet, Thomas, Craig J, Starczynowski, Daniel T. . Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML. In Blood, 142, 989-1007. doi:10.1182/blood.2022018718. https://pubmed.ncbi.nlm.nih.gov/37172199/

5. Hosseini, Najme, Tahoori, Mohammad Taher, Mohammadzadeh, Adel, Bitaraf Sani, Morteza, Soleimani Salehabadi, Hosein. 2020. IRAK1 Gene Polymorphism in Rheumatoid Arthritis. In Immunological investigations, 50, 304-321. doi:10.1080/08820139.2020.1764028. https://pubmed.ncbi.nlm.nih.gov/32507051/