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Chemotherapeutics treatment led to the Ca2+ overload and MAPKs activation, resulting in DNA damage and cell death ultimately in both HCC cells and hepatic cells. Meanwhile, the expression of mGlu5 in HCC cells was downregulated in response to chemotherapeutics, and inhibition of mGlu5 aggravated the cytotoxicity of chemotherapeutics but the agonist of mGlu5 reversed this effect. Unlike HCC cells, chemotherapeutics upregulated the expression of mGlu5 in hepatic cells, and the inhibition of mGlu5 resisted the hepatotoxicity.