The article by Bristy Basak and Sachiko Akashi-Takamura from Aichi Medical University reviews the role of IRF3 in sepsis and the current gaps in sepsis immunology. Lipopolysaccharide (LPS) induces potent cell activation through Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2), leading to septic death and cytokine storms. TLR4 signaling activates both the classical acute innate immune pathway via MyD88 and the non-canonical pathway via TRIF, resulting in pro-inflammatory cytokine production and nuclear transcription factor changes. IRF3, a transcription regulator, is activated by phosphorylation and dimerization after microbial infection, leading to the production of type 1 interferons (IFNs) and antiviral genes. IRF3-deficient mice are resistant to LPS-induced endotoxin shock, and IRF3 inhibitors have shown potential in reducing septic shock. The gut microbiota also plays a crucial role in sepsis, with IRF3 enhancing pathogen clearance and influencing gut homeostasis. However, there are still significant gaps in sepsis immunology, including the understanding of differential tissue responses, cell metabolism, epigenetic mechanisms, and the impact of microbiota on immunity. Addressing these gaps is essential for improving the prevention, diagnosis, and treatment of sepsis.The article by Bristy Basak and Sachiko Akashi-Takamura from Aichi Medical University reviews the role of IRF3 in sepsis and the current gaps in sepsis immunology. Lipopolysaccharide (LPS) induces potent cell activation through Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2), leading to septic death and cytokine storms. TLR4 signaling activates both the classical acute innate immune pathway via MyD88 and the non-canonical pathway via TRIF, resulting in pro-inflammatory cytokine production and nuclear transcription factor changes. IRF3, a transcription regulator, is activated by phosphorylation and dimerization after microbial infection, leading to the production of type 1 interferons (IFNs) and antiviral genes. IRF3-deficient mice are resistant to LPS-induced endotoxin shock, and IRF3 inhibitors have shown potential in reducing septic shock. The gut microbiota also plays a crucial role in sepsis, with IRF3 enhancing pathogen clearance and influencing gut homeostasis. However, there are still significant gaps in sepsis immunology, including the understanding of differential tissue responses, cell metabolism, epigenetic mechanisms, and the impact of microbiota on immunity. Addressing these gaps is essential for improving the prevention, diagnosis, and treatment of sepsis.