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 in vivo and in silico studies

Objective(s): 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 Schr & ouml;dinger 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 (P<0.05) alleviated these alterations. Mechanistically, SA down-regulated the HMGB1/TLR4/NF-kappa B signaling cascade and activated the Keap1/Nrf2/HO-1 antioxidant pathway. Reduced 8-OHdG and caspase-3 expression indicated mitigation of oxidative DNA damage and apoptosis. Docking analysis revealed strong binding affinity and favorable MM-GBSA scores for SA within the KEAP1 active pocket, suggesting direct modulation of Nrf2 activation. Conclusion: SA confers potent protection against LPS-induced ALI through coordinated antiinflammatory and antioxidant mechanisms involving HMGB1/TLR4/NF-kappa B inhibition and Keap1/ Nrf2/HO-1 activation. These findings highlight SA as a promising therapeutic candidate for sepsisassociated pulmonary injury.