The MicroRNA network in sepsis: from biomarker discovery to novel targeted therapeutic strategies

Sepsis is a life-threatening multiple-organ dysfunction syndrome triggered by infection and mediated by host immune dysregulation. Its complex pathophysiological mechanisms and the lack of effective diagnostic and therapeutic approaches make it a major challenge for the global healthcare system. As key molecules in post-transcriptional gene regulation, microRNAs (miRNAs) play crucial roles in immune dyshomeostasis, inflammatory storms, and organ damage during sepsis, and have emerged as a research focus in this field in recent years. This review summarizes the research progress of miRNAs in sepsis, with a focus on their expression characteristics, regulatory mechanisms, and clinical translational value. miRNAs regulate inflammatory responses by targeting core signaling pathways such as the Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) pathway. The specific mechanisms include: blocking upstream pathway activation by targeting TLR ligands or adaptor proteins; directly regulating NF-κB subunits to inhibit the transcription of pro-inflammatory genes; modulating negative feedback loops; and interacting with other signaling cascades. Furthermore, certain miRNAs act as both key regulators of immune responses and potential diagnostic/prognostic biomarkers. In terms of organ damage, miRNAs display organ-specific characteristics by working as specific regulatory molecules in sepsis-associated cardiac, hepatic, and cerebral injuries. They affect organ function by targeting pathways such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT). In terms of clinical translational value, miRNAs derived from human serum/plasma have shown significant potential in sepsis diagnosis, treatment guidance, and prognosis prediction. By dissecting the regulatory network of miRNAs in sepsis, this review not only provides a theoretical basis for understanding the complex pathophysiology of sepsis but also identifies key directions for developing miRNA-based precision diagnostic and therapeutic strategies (e.g. combined detection of multiple biomarkers and targeted delivery systems). It is anticipated to offer novel solutions for improving the prognosis of sepsis patients and reducing mortality.