Drug-induced liver injury (DILI) is a common adverse reaction in the course of clinical drug treatment, which is mainly characterized by hepatocellular death, hepatic function impairment, and even acute liver failure. Acetaminophen (APAP) is one of the most widely used antipyretic and analgesic drugs in the world. Although APAP is a very safe drug approved by the U.S. Food and Drug Administration (FDA), liver injury caused by APAP is extremely common, accounting for more than 50% of drug-induced liver injuries. After entering the liver, APAP is catalyzed by cytochrome P4502E1 (cytochrome P450, family 2, subfamily E, polypetide 1; CYP2E1) to produce a highly reactive and toxic intermediate metabolite, N-acetyl-p-benzoquinoneimine (N-acetyl-p-aminophenol, NAPQI). Under normal conditions, NAPQI is reduced to non-toxic thiol and cysteine products by glutathione (GSH). When APAP is overdosed, a large amount of NAPQI leads to hepatocyte death, which in turn triggers an intense hepatic inflammatory response, ultimately leading to liver failure. Therefore, inhibition of the over-activated hepatic inflammatory response is considered as a potential target for the treatment of APAP-induced drug-induced liver injury.

Kupffer cells are liver resident macrophages, accounting for about 20% of liver nonparenchymal cells, which can recognize a large number of signaling molecules of internal and external origin, initiate hepatic inflammatory responses, and play a crucial role in maintaining liver homeostasis.Kupffer cells play an important role in a variety of acute and chronic liver diseases, such as acute viral hepatitis, drug overdose, and ischemia-reperfusion (IR), trichloroethylene (TCE) allergy syndrome, non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). However, the role of Kupffer cells in APAP-induced drug-induced liver injury has been controversial. Earlier, Laskin et al. and Michael et al. significantly reduced APAP hepatotoxicity by pretreating rats and mice with gadolinium chloride (GdCl3). Subsequent studies have shown that the use of liposome-encapsulated chlorophosphate (clodrosome, CLO) to pre-clear Kupffer cells may exacerbate liver injury or have no effect. Fundamentally, both of these research tools for culling Kupffer cells remain controversial in their own right.

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