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Infection and/or drug-mediated acute liver injury, the leading cause of lethal liver failure, is a critical health problem worldwide and lacks effective treatment. Here, we used Lipopolysaccharides (LPS)/D-galactosamine (D-gal)-treated primary hepatocytes to screen a natural library that contains 1130 chemicals. Baicalein in the library showed highest inhibitory effects against LPS/D-Gal-induced liver injury. In-vivo study similarly validated the protection of baicalein against dampened liver function and increased lethality after a challe