cGAS-STING targeting offers novel therapeutic regimen in sepsis-associated organ dysfunction

Abstract

Sepsis is clinically defined as a life-threatening syndrome characterized by dysregulated host responses to infection, culminating in progressive multi-organ dysfunction. The pathogenesis of sepsis-associated organ dysfunction (SAOD) -manifesting as encephalopathy, cardiomyopathy, acute kidney/liver injury, and respiratory failure-represents the primary determinant of mortality in septic patients. Despite its clinical significance, the molecular mechanisms driving SAOD remain incompletely elucidated. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis is a critical innate immune pathway by triggering a type I interferon (IFN-I) response. However, aberrant activation of this axis leads to inflammatory and autoimmune diseases.Emerging evidence implicates hyperactivation of cGAS-STING as a critical mediator of SAOD across multiple organ systems. Notably, pharmacological inhibitors targeting cGAS-STING signaling demonstrate therapeutic promise in preclinical models of sepsis-induced organ injury, attenuating inflammatory cascades and preserving tissue integrity. This review synthesizes current insights into the mechanistic contributions of cGAS-STING signaling to SAOD pathogenesis while critically evaluating novel therapeutic agents-including small -molecule inhibitors, natural compounds, and biologics-that disrupt this pathway to mitigate organ dysfunction. By bridging molecular mechanisms with translational applications, we underscore cGAS-STING inhibition as a paradigm-shifting strategy for addressing the unmet clinical needs in sepsis and SAOD management.

Keywords: CGAS; CGAS-STING inhibitor; Organ dysfunction; STING; Sepsis.