Natural Products That Protect Against Acetaminophen Hepatotoxicity: A Call for Increased Rigor in Preclinical Studies of Dietary Supplements

Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury. The current standard-of-care treatment for APAP hepatotoxicity, <i>N</i>-acetyl-<i>l</i>-cysteine, is highly effective when administered early after overdose, but loses efficacy in later-presenting patients. As a result, there is interest in the identification of new treatments for APAP overdose patients. Natural products are a promising source of new treatments because many are purported to have hepatoprotective effects. In fact, a great deal of research has been done to identify natural products that can protect against APAP-induced liver injury. However, serious concerns have been raised about the rigor and human relevance of these studies. Here, we systematically reviewed the APAP-natural product literature from 2013 to 2023 to determine the veracity of these concerns and the scope of the potential problem. The results substantiate the concerns that have been previously raised and point to concrete steps that can be taken to improve APAP-natural product research.