Remifentanil attenuates LPS-induced hepatic injury by modulating NRF2/HO-1 and necroptosis-related gene expression

Lipopolysaccharide (LPS)-induced sepsis causes widespread inflammation and liver dysfunction, driven by oxidative stress and necroptosis. Remifentanil (REM), a short-acting μ-opioid receptor (MOR) agonist, has demonstrated anti-inflammatory and antioxidant effects. This study aimed to assess its potential hepatoprotective role in an LPS-induced rat model of liver injury. Female Wistar rats were allocated into four groups: Control, LPS (5 mg/kg, intraperitoneally), LPS + REM (LPS plus 0.04 mg/kg total dose of REM via IV infusion over 40 min), and REM alone. Liver tissues were analyzed histologically and immunohistochemically for tumor necrosis factor-alpha (TNF-α), alkaline phosphatase (ALP), and hypoxia-inducible factor-1 alpha (HIF-1α). Biochemical analyses included aspartate transaminase (AST), alanine transaminase (ALT), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI). Expression levels of nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL) were assessed by qRT-PCR. LPS induced significant liver damage, as evidenced by higher histopathological scores, elevated liver enzymes, oxidative imbalance, and upregulated necroptotic gene expression. REM significantly reduced inflammation, necrosis, and hemorrhage. ALP expression remained comparable to the control group, whereas HIF-1α and TNF-α were markedly reduced. REM showed a non-significant decreasing trend in AST, ALT, TOS, and OSI levels. In contrast, REM significantly restored NRF2 and HO-1 mRNA expression and reduced the mRNA expression of RIPK1, RIPK3, and MLKL. REM attenuated LPS-induced hepatic injury, and this effect was found to be associated with modulation of oxidative stress responses, inflammatory alterations, and necroptosis-related gene expression. These findings suggest that REM may have potential as an adjunctive pharmacological agent in sepsis-associated hepatic dysfunction; however, further protein-level and pathway-specific validation studies are required.