Abstract Background Sepsis-associated acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent the most lethal manifestations of dysregulated systemic inflammation. Despite decades of research, no approved pharmacologic therapies directly target the inflammatory and epithelial-endothelial injury pathways that drive sepsis-related respiratory failure. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for diabetes, exert potent anti-inflammatory, antioxidative, and cytoprotective actions that may interrupt these injury cascades. This systematic review synthesizes experimental evidence evaluating the role of GLP-1RAs in preventing or mitigating sepsis-associated ALI. Methods Following PRISMA 2020 guidelines, PubMed, Embase, and Scopus were searched through October 2025 for preclinical or clinical studies assessing GLP-1 analogs (liraglutide, dulaglutide, semaglutide, exenatide) in sepsis or pneumonia-related lung injury. Eligible studies examined outcomes related to pulmonary inflammation, surfactant function, oxidative stress, vascular injury, or clinical respiratory endpoints. Mechanistic pathways were categorized into immune modulation, oxidative stress, apoptosis, and epithelial barrier preservation. Results Five studies met inclusion criteria (four translational, one large human cohort). Across murine models of endotoxemia, cecal slurry-induced sepsis, and pneumonia-sepsis, GLP-1RA treatment consistently reduced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) by 40-70%, suppressed NLRP3/STAT3 signaling, and inhibited apoptosis and autophagy (↓ markers: caspase-3, Bax/Bcl-2, Beclin-1, LC3). Liraglutide and dulaglutide improved surfactant protein (SP-A/SP-B) synthesis, preserved alveolar-capillary integrity, decreased lung edema, and enhanced survival by 25-50%. Mechanistically, GLP-1 receptor activation attenuated oxidative stress and restored endothelial function through downregulation of iNOS and reactive nitrogen species. The only clinical study demonstrated a ∼40% reduction in incident pneumonia and severe sepsis among GLP-1RA users, suggesting potential translational relevance. Conclusions Evidence from translational and observational studies indicates that GLP-1 receptor agonists mitigate sepsis-associated ALI by attenuating inflammation, oxidative stress, and apoptosis, while promoting surfactant homeostasis and vascular barrier function. GLP1-RAs appear to stabilize both vascular and epithelial compartments of the lung microenvironment, thereby improving host resilience to infection-induced injury. These findings identify GLP-1 signaling as a promising immunometabolic therapeutic target for sepsis-related respiratory failure. Future prospective randomized trials are warranted to define optimal dosing, timing, and patient selection for GLP-1RA use in this subgroup. This abstract is funded by: None
Chilingarashvili et al. (Fri,) studied this question.