Oncogenic IRF3 Signaling Promotes Diffused Large B-Cell Lymphoma Proliferation by Cyclin D3/CDK4-Dependent Cell Cycle Control

Diffuse large B-cell lymphoma (DLBCL), the most aggressive non-Hodgkin lymphoma subtype, is cured in 60%–70% of patients with frontline chemoimmunotherapy. For refractory/relapsed cases, deciphering DLBCL's molecular drivers could unveil new therapies to overcome resistance and enhance survival. Interferon regulatory factor 3 (IRF3) is a transcription factor that drives type I interferon responses, crucial for antiviral defense against DNA and RNA viruses. Emerging evidences implicate IRF3 in the malignant progression of gastric cancer, hepatocellular carcinoma, and multiple myeloma. However, its biological role and prognostic significance in DLBCL need further investigation. Here, we examined the expression level of IRF3 in DLBCL patient samples. Functional impact on proliferation was assessed by MTS and EdU assays, while mechanistic insights were obtained through cell cycle analysis and apoptosis evaluation. As a result, IRF3 expression was significantly elevated in DLBCL patients compared to controls and correlated with poorer clinical outcomes. Notably, increased expression of IRF3 induced by poly I:C or poly dA:dT enhanced DLBCL cells proliferation, whereas IRF3 knockdown suppressed this effect. Furthermore, IRF3 promoted G1/S phase transition by upregulating cyclin D3 and CDK4 expression. Collectively, IRF3 regulates DLBCL cell proliferation by controlling G1/S transition via cyclin D3 and CDK4. Thus, our study identifies IRF3 as a novel regulator of DLBCL proliferation, highlighting its potential as a therapeutic target in DLBCL.