Abstract
<title>Abstract</title> <p>Background Acute respiratory distress syndrome (ARDS) is a life-threatening clinical syndrome characterized by acute hypoxemic respiratory failure, with mortality rates ranging from 30% to 50% in critically ill patients. Despite decades of research, effective targeted therapies remain limited. Metabolic reprogramming and excessive neutrophil-mediated inflammation are central pathological features of ARDS, yet the underlying regulatory mechanisms remain incompletely understood. Methods RNA sequencing (RNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from 6 healthy donors, 13 ARDS patients, and 4 post-ARDS patients. A mouse model of ARDS was established via lung contusion. Fructose and mannose levels, as well as the expression of related metabolic genes, were measured using biochemical assays, quantitative real-time PCR, and Western blotting. Virtual screening was conducted to identify potential PFKFB2-targeted compounds. The therapeutic effects of pentagalloylglucose (PGG) were evaluated using histopathology, lung function tests, enzyme-linked immunosorbent assay, flow cytometry, and Seahorse extracellular flux analysis. RNA interference and overexpression techniques were employed to verify the regulatory role of PFKFB2. Results ARDS patients and mice exhibited elevated fructose levels, reduced mannose levels, and increased expression of PFKFB2, PFKFB3, PFKFB4, GFUS, and HK3 in peripheral blood and neutrophils, with PFKFB2 being the most prominently upregulated key gene. PGG was identified as a potent PFKFB2 inhibitor that directly binds to PFKFB2 and inhibits its expression in a dose- and time-dependent manner. In ARDS mice, PGG treatment significantly attenuated lung tissue damage, improved pulmonary function, reduced the secretion of pro-inflammatory cytokines (MCP-1, TNF-α, IL-1β, IL-6), and corrected abnormal neutrophil accumulation. Mechanistically, PGG suppressed neutrophil glycolysis and inflammatory cytokine production by inhibiting PFKFB2-mediated fructose metabolism. Conclusions PFKFB2 is a critical driver of ARDS pathogenesis by promoting neutrophil glycolysis and excessive inflammation. PGG exerts robust protective effects against ARDS by directly targeting PFKFB2, providing a novel therapeutic target and strategy for the treatment of this devastating syndrome.</p>