Decoding Sepsis: Unraveling Key Signaling Pathways for Targeted Therapies

Sepsis is a complex clinical syndrome marked by dysregulated immune responses, systemic inflammation, and subsequent organ dysfunction. Sepsis involves the interplay of multiple signaling pathways. Traditional sepsis treatment mainly depends on antibiotics and early directed therapy, with limited effectiveness. This article reviews major signaling pathways in sepsis, such as those related to nuclear factor κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), Toll-like receptors (TLRs), mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1α (HIF-1α), and nuclear factor-erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1). These molecules are pivotal in regulating immune activation, inflammation, and immune cell metabolism. Moreover, mitochondrial dysfunction and metabolic reprogramming substantially contribute to sepsis development, as they greatly affect energy production and immune cell function. Selectively inhibiting these pathways shows potential for effectively reducing hyperinflammation and preventing organ failure. We discussed how future research on these signaling pathways can translate into clinical applications and how personalized treatment strategies can handle the complexity and variability of sepsis. Given the dynamic nature of sepsis, treatment strategies should not solely rely on traditional single-target interventions. Instead, a dynamic and personalized multi-target modulatory approach is needed. While reducing side effects of single-target inhibition, inflammatory responses, immune balance, and metabolic disorders can be more precisely regulated. By precisely monitoring multiple sepsis-related signaling pathways and adjusting treatment regimens in real time, we aim to identify more effective intervention points in the complex dynamics of diseases, thus providing new hope for improving prognosis of septic patients.