The Natural Compound Cornuside Protects Against Acute Liver Failure Induced by Lipopolysaccharide and D-Galactosamine

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Abstract
Purpose: Acute liver failure (ALF) is a life-threatening syndrome characterized by rapid hepatocyte injury, excessive inflammation, and oxidative stress. Cornuside, an iridoid glycoside derived from Cornus officinalis Sieb. et Zucc, has been reported to exert anti-inflammatory and antioxidant activities, but its role in ALF remains unclear. This study aimed to evaluate the preventive and therapeutic effects of cornuside in a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced mouse ALF model and to explore the underlying mechanisms. Methods: ALF was induced in mice by intraperitoneal injection of LPS and D-GalN. Cornuside was administered via tail vein injection either 3 h before or 1 h after LPS/D-GalN administration to assess its preventive and post-injury therapeutic effects, respectively. Serum and liver tissues were harvested 12 h after LPS/D-GalN challenge for the assessment of liver injury, hepatocyte apoptosis, intrahepatic immune cell activation, inflammatory cytokine production, oxidative stress, and ferroptosis-associated markers. Results: Cornuside administration after LPS/D-GalN challenge did not produce significant therapeutic protection against established ALF. In contrast, cornuside pretreatment markedly reduced serum alanine aminotransferase and aspartate aminotransferase levels, alleviated hepatic histopathological injury, and decreased hepatocyte apoptosis. Cornuside pretreatment also suppressed intrahepatic immune cell activation and reduced pro-inflammatory cytokine production. Moreover, cornuside attenuated oxidative stress, as indicated by reduced lipid peroxidation and enhanced antioxidant activity. Mechanistically, cornuside pretreatment modulated ferroptosis-associated signaling, including downregulation of ACSL4 and upregulation of xCT and Gpx4, suggesting that inhibition of ferroptosis may contribute to its hepatoprotective effects. Conclusion: Cornuside provided significant preventive protection against LPS/D-GalN-induced ALF. This protection may be associated with inhibition of inflammation, oxidative stress, and ferroptosis-related ACSL4/xCT/Gpx4 signaling, suggesting cornuside as a potential preventive candidate for ALF. The diagram illustrates the protective effects of cornuside against acute liver failure (ALF). Cornuside alleviates liver injury through three main mechanisms. First, it modulates immune and inflammatory responses by suppressing NKT cells, NK cells, activated T cells, and macrophages, while increasing the proportion of MDSCs. It also downregulates the expression of inflammatory cytokines, including IL-12/p40, IL-6, and TNF-α. Second, cornuside reduces oxidative stress by increasing GSH and SOD levels and decreasing MPO, LPO, MDA, and Fe levels. Third, cornuside inhibits ferroptosis by regulating the ACSL4/xCT/Gpx4 signaling pathway. Specifically, it decreases ACSL4 expression and increases xCT and Gpx4 expression, thereby suppressing ferroptosis and ultimately alleviating ALF.Cornuside aids acute liver failure by suppressing immunity, reducing oxidative stress and inhibiting ferroptosis.

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