Hepatoprotective Effects of Flavonoids Against Acetaminophen Toxicity

Acetaminophen (APAP) is a common analgesic and antipyretic agent; however, overdose can cause severe liver injury requiring transplantation or resulting in death. Currently, N-acetylcysteine (NAC) is the standard first-line treatment for APAP-induced liver injury (AILI). There is ongoing interest in exploring complementary hepatoprotective compounds, such as plant-derived flavonoids and their mechanisms of action to improve our understanding and management of AILI. This review aims to identify key flavonoids studied to date in the setting of AILI and their proposed mechanisms. A systematic search was conducted across PubMed, Scopus, Web of Science, and Embase. Eligible studies were restricted to murine models of APAP overdose where isolated flavonoids were administered therapeutically post-APAP-injury. From 1752 identified records, 18 studies investigating sixteen distinct flavonoids met the inclusion criteria. Their major mechanisms of actions were identified which include antioxidation, anti-inflammation, modulation of APAP metabolism, and inhibition of cell death pathways. Furthermore, emerging nano-delivery systems markedly enhanced flavonoid solubility and therapeutic efficacy. Although these findings highlight promising candidates and novel therapeutic targets for AILI, clinical trials are essential to establish human efficacy and safety.