Gallic acid attenuates LPS-induced hepatic injury via SIRT-1–dependent immunomodulation and anti-apoptotic mechanisms in rats

Sepsis-related hepatic injury arises from intertwined inflammatory, oxidative, and apoptotic mechanisms. This study aimed to evaluate the hepatoprotective effects of gallic acid (GA), a natural polyphenol, in a lipopolysaccharide (LPS)-induced rat model, with a particular focus on the SIRT-1/p53 axis and mitochondrial stress. Thirty-two adult male Wistar rats were divided into four groups (Control, LPS, GA + LPS, and GA; n = 8 each). GA (100 mg/kg, endotoxin-free, ≥98% purity; Sigma-Aldrich, USA) or saline was administered intraperitoneally 15 min before LPS (5 mg/kg, Escherichia coli O111:B4). Six hours after induction, liver tissues were examined histopathologically, and immunohistochemical expression of interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR-4) was assessed, along with transcriptional levels of p53, sirtuin-1 (SIRT-1), BCL-2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and caspase-3 (CAS-3) using reverse transcription polymerase chain reaction. Serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were also measured biochemically. LPS administration caused severe hepatic injury characterized by congestion, hemorrhage, neutrophil infiltration, necrosis, and elevated AST/ALT levels, accompanied by upregulation of IL-6, NF-κB, TLR-4, and pro-apoptotic genes, and downregulation of SIRT-1 and BCL-2. GA co-treatment significantly ameliorated these alterations, reducing inflammatory and apoptotic markers, restoring SIRT-1, and suppressing p53 activation. Collectively, GA exerts hepatoprotective effects through modulation of the TLR-4/NF-κB/IL-6 pathway and restoration of the SIRT-1/p53 regulatory axis, highlighting its immunopharmacological potential in sepsis-induced hepatic dysfunction.