Isoferulic acid alleviates LPS/D-galactosamine-induced acute liver injury in mice by inhibiting ERK/NF-κB signaling and modulating the NLRP3 inflammasome.

Isoferulic acid, a bioactive constituent derived from Cimicifuga species, is structurally related to ferulic acid, a compound known for its hepatoprotective properties. Despite this similarity, its potential role in acute liver injury and the associated molecular mechanisms have not been fully clarified. In the present study, we investigated the protective effects of isoferulic acid in a murine model of acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Isoferulic acid (10, 30, or 60 mg/kg) was administered after LPS/D-GalN challenge. Treatment markedly alleviated liver injury, as reflected by a dose-dependent decrease in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)levels, along with improvement in histopathological features. Isoferulic acid also reduced oxidative stress in hepatic tissue, evidenced by lower malondialdehyde (MDA) levels, and attenuated the production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and interferon (IFN)-γ. Further analysis indicated that these protective effects were associated with suppression of extracellular signal-regulated kinase (ERK) phosphorylation and inhibition of nuclear factor-kappa B (NF-κB) nuclear translocation, suggesting modulation of key inflammatory signaling pathways. In addition, isoferulic acid reduced NLRP3 expression and IL-1β production, suggesting modulation of NLRP3 inflammasome-associated responses. Collectively, these findings indicate that isoferulic acid protects against LPS/D-GalN-induced acute liver injury by reducing oxidative stress and inhibiting ERK/NF-κB and modulating NLRP3 inflammasome-associated responses. Isoferulic acid may represent a potential therapeutic candidate for acute liver failure.