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

Articles in Press

Document Type : Original Article

Authors

1 Department of Physiology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey

2 Department of Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, Turkey

3 Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey

4 Department of Pathology, Faculty of Veterinary Medicine, Kyrgyzstan-Turkey Manas University, Bishkek, Kyrgyzstan

5 Department of Biochemistry, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt

10.22038/ijbms.2026.90093.19427

Abstract

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 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 (P<0.05) alleviated these alterations. Mechanistically, SA down-regulated the HMGB1/TLR4/NF-κB 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 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.

Keywords

Main Subjects

References

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Iranian Journal of Basic Medical Sciences

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Available Online from 06 January 2026

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