Syringic acid attenuates LPS-induced acute lung injury via modulation of the HMGB1/TLR4/NF-κB and Keap1/Nrf2/HO-1 pathways: Mechanistic insights from

Objectives: Sepsis-induced acute lung injury (ALI), driven by uncontrolled inflammation and oxidative stress, remains a major cause of mortality in critically ill patients. This study aimed to investigate the protective and mechanistic effects of syringic acid (SA), a natural phenolic compound, against lipopolysaccharide (LPS)-induced ALI in rats. Materials and Methods: Male Sprague-Dawley rats were allocated into five groups: control, SA80, LPS, SA40+LPS, and SA80+LPS. SA was orally administered (40 or 80 mg/kg/day) for 14 days before a single intraperitoneal injection of LPS (10 mg/kg). Lung tissues were collected 12 hr post-LPS for histopathological, biochemical, and molecular evaluations. In silico docking using Schrödinger Maestro (2025/1) assessed SA interaction with the KEAP1 Kelch domain (PDB: 5FZN). Results: LPS challenge caused severe pulmonary edema, inflammatory infiltration, elevated proinflammatory cytokines, lipid peroxidation, and reduced antioxidant enzyme activities. SA pretreatment, particularly at 80 mg/kg, significantly ( Conclusion: SA confers potent protection against LPS-induced ALI through coordinated anti-inflammatory and antioxidant mechanisms involving HMGB1/TLR4/NF-κB inhibition and Keap1/Nrf2/HO-1 activation. These findings highlight SA as a promising therapeutic candidate for sepsis-associated pulmonary injury.