Syringic acid attenuates LPS-induced acute lung injury via modulation of the HMGB۱/TLR۴/NF-κB and Keap۱/Nrf۲/HO-۱ 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, SA۸۰, LPS, SA۴۰+LPS, and SA۸۰+LPS. SA was orally administered (۴۰ or ۸۰ mg/kg/day) for ۱۴ days before a single intraperitoneal injection of LPS (۱۰ mg/kg). Lung tissues were collected ۱۲ hr post-LPS for histopathological, biochemical, and molecular evaluations. In silico docking using Schrödinger Maestro (۲۰۲۵/۱) assessed SA interaction with the KEAP۱ Kelch domain (PDB: ۵FZN).Results: LPS challenge caused severe pulmonary edema, inflammatory infiltration, elevated proinflammatory cytokines, lipid peroxidation, and reduced antioxidant enzyme activities. SA pretreatment, particularly at ۸۰ mg/kg, significantly (P<۰.۰۵) alleviated these alterations. Mechanistically, SA down-regulated the HMGB۱/TLR۴/NF-κB signaling cascade and activated the Keap۱/Nrf۲/HO-۱ antioxidant pathway. Reduced ۸-OHdG and caspase-۳ expression indicated mitigation of oxidative DNA damage and apoptosis. Docking analysis revealed strong binding affinity and favorable MM-GBSA scores for SA within the KEAP۱ active pocket, suggesting direct modulation of Nrf۲ activation.Conclusion: SA confers potent protection against LPS-induced ALI through coordinated anti-inflammatory and antioxidant mechanisms involving HMGB۱/TLR۴/NF-κB inhibition and Keap۱/Nrf۲/HO-۱ activation. These findings highlight SA as a promising therapeutic candidate for sepsis-associated pulmonary injury.

کلیدواژه ها:

Acute lung injury ، Inflammation ، Lipopolysaccharide ، NF-kappa B ، Oxidative stress ، Phenols