Astragalin protects against lipopolysaccharide-triggered acute liver injury through suppression of necroptosis and inflammation and improvement of energy metabolism

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• Astragalin (AST) ameliorated the inflammatory and pathological changes as well as functional abnormalities of lipopolysaccharide (LPS)-induced acute liver injury. • AST inhibited the tumor necrosis factor (TNF)-α-driven receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis signaling pathway. • AST suppressed the activation of the hypoxia-inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) signaling pathway. • AST hindered the enhanced glycolysis of M1 macrophages. Acute liver injury (ALI) is a prevalent clinical condition featured by liver inflammation and functional abnormalities resulting from various causes. Prolonged damage to liver cells can progress to chronic inflammation, fibrosis, and cirrhosis. Astragalin (AST), a natural flavonoid present in traditional medicinal and edible plants, exhibits anti-inflammatory and antioxidative properties, making it a potential therapeutic candidate for ALI. Using network pharmacology analysis, we explored the targets and pathways implicated in the regulation of AST against ALI. Our study using an ALI mouse model showed that AST effectively mitigates oxidative stress and inflammation induced by lipopolysaccharide (LPS), offering protection against LPS-induced ALI. The mechanism may involve inhibiting the tumor necrosis factor-α-driven necroptosis pathway and downregulating the hypoxia-inducible factor-1α/pyruvate kinase M2 signaling pathway, thereby suppressing enhanced glycolysis-mediated inflammatory response. Through the synergistic modulation of multiple targets and pathways, AST emerges as a promising therapeutic option for ALI, offering potential for clinical application.