Research progress on the mechanism of FOXO protein in sepsis.

Sepsis has a high morbidity and mortality rate, and effective therapeutic options remain limited. Lipopolysaccharide (LPS) is known to induce significant changes in the expression of forkhead box O (FOXO) transcription factor family members, and the mechanisms by which various drugs, including dexamethasone, treat sepsis are associated with the FOXO signaling pathway. Increased FOXO3 expression can reduce levels of inflammatory mediators, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), by more than one-third. However, FOXO proteins not only regulate inflammatory activity but also function as transcription factors with important roles across various tissues. The FOXO transcription factor family participates in cell-cycle regulation, apoptosis, autophagy, stress responses, DNA repair, tumorigenesis, and metabolism. Current research shows that FOXO proteins affect the occurrence, progression, and prognosis of sepsis by regulating several processes, including pro- and anti-inflammatory responses, immune regulation, oxidative stress, mitochondrial activity, vascular injury, and gut microbiota translocation. With improved understanding of FOXO-related mechanisms, researchers have proposed several strategies for therapeutic development targeting FOXO. These approaches include targeting upstream post-translational modifications, designing small-molecule agents that act on FOXO, regulating downstream proteins, and applying multi-target intervention strategies. These directions offer new possibilities for sepsis treatment.