Omega-3 pretreatment attenuates hepatic inflammatory histopathology in LPS-Induced rat endotoxemia: exploratory SIRT1/HO-1 findings.

Sepsis is a major global contributor to morbidity and mortality, and liver dysfunction intensifies disease severity. Lipopolysaccharide (LPS)-induced liver injury is characterized by inflammation, oxidative stress, and apoptosis, whereas the sirtuin-1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway provides essential cellular protection. Although omega-3 (OMG3) polyunsaturated fatty acids are recognized for their anti-inflammatory and antioxidant properties, their effects on this pathway remain unclear. This study investigated the hepatoprotective effects of OMG3 pretreatment against LPS-induced hepatic injury in rats, evaluating histopathological injury as the primary endpoint together with hepatic SIRT1, NRF2, and HO-1 expression, inflammatory/apoptotic markers, and redox status as secondary/exploratory outcomes. Thirty-two female Wistar Albino rats were assigned to four groups: control, LPS (5 mg/kg, i.p.), LPS + OMG3, and OMG3 (0.5 g/kg/day, i.p.). Liver tissues were analyzed by histopathology, immunohistochemistry, RT-qPCR, and oxidative stress assays, including total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI). LPS produced significant histopathological damage (hemorrhage, inflammation, and necrosis scores; all p ≤ 0.003 vs. control), increased immunoreactivity of Caspase-3, NF-κB, TNF-α, and VEGF (all p ≤ 0.005), decreased hepatic SIRT1 and HO-1 mRNA expression (p = 0.015, p = 0.009), and elevated OSI (p < 0.001). Three-day OMG3 pretreatment significantly reduced the histopathological inflammation score versus LPS (adjusted p = 0.037); reductions in hemorrhage and necrosis scores, Caspase-3/NF-κB/TNF-α/VEGF immunoreactivity, SIRT1/HO-1 mRNA expression, and TAS/OSI were directionally favorable but did not reach significance (adjusted p = 0.050-0.763). NRF2 expression and TOS did not differ among groups. Under this prophylactic regimen, 3-day OMG3 pretreatment significantly attenuated the histopathological inflammatory response to acute LPS-induced hepatic injury. Reductions in apoptotic, inflammatory, and angiogenic immunoreactivity, hepatic SIRT1/HO-1 expression, and redox indices were directionally consistent but statistically unconfirmed in the LPS + OMG3-versus-LPS comparison, and should be interpreted as exploratory. Activation of the SIRT1-NRF2/HO-1 pathway was not established at the protein level, and further dose-ranging and mechanistic studies are needed before extrapolating these findings to a therapeutic context.