Advances on botanicals targeting programmed cell death in acetaminophen-induced liver injury

Acetaminophen (APAP), a widely used analgesic and antipyretic drug, poses a significant clinical challenge worldwide due to its potential to induce hepatotoxicity following overdose. At present, limited therapeutic options exist for APAP overdose. Moreover, N-acetylcysteine (NAC), the first-line clinical agent in routine use, suffers from a narrow therapeutic window and numerous adverse effects, which limits its clinical utility. Plants constitute a rich reservoir of phytochemicals that engage in multiple pharmacological processes, positioning them as a cornerstone in pharmaceutical innovation. The therapeutic use of herbs for liver conditions is historically recognized in classical works such as the "Treatise on Febrile Diseases," "Compendium of Materia Medica," and "Thousand Golden Prescriptions."

Chinese herbal medicines and their extracts have garnered significant attention for the prevention and treatment of acetaminophen (APAP)-induced liver injury (AILI), largely due to their therapeutic efficacy and favorable safety profile. The programmed cell death (PCD) induced by APAP, and the impact and potential mechanism on the pathogenesis of AILI are discussed in this review. Furthermore, various botanicals that can be used to prevent AILI, as well as the structure-activity relationships and potential mechanisms, are discussed.

Articles published over the past decade were retrieved from databases including Web of Science, PubMed, and CNKI, using the keywords APAP, AILI, natural products, and traditional Chinese medicine. Studies that failed to clearly characterize the components of plant extracts were excluded. Subsequently, a preliminary classification was performed based on the chemical structures of the included natural products, with priority given to relatively novel agents supported by robust research data or notable research advances. Following a systematic review and synthesis of key study details, including experimental design, phenotypic alterations, and mechanism elucidation, the decision was made to conduct further in-depth analysis focusing on the type of PCD. Ultimately, more than 160 papers were selected and discussed in this review.

A systematic review of the literature identified plant extracts with anti-AILI properties, which can be categorized into nine distinct classes based on their bioactive structures. By comparing the experimental research evidence from 44 natural compounds, not only were several more promising compounds such as sinomenine, dihydromyricetin, tannic acid and pterostilbene obtained, but it also helped to clarify the protective mechanisms of these extracts. Studies have found that numerous derivatives of natural products are capable of concurrently modulating multiple signaling pathways, such as Nrf2-HO1, NF-κB, and RIPK/MLKL, to alleviate PCD caused by APAP, thereby offering potential strategies for the prevention or treatment of AILI.

This review systematically elucidates the mechanisms by which structurally diverse phytochemicals alleviate APAP-induced hepatotoxicity, with a specific focus on their modulatory roles in programmed cell death pathways implicated in AILI. These findings provide valuable insights for the development of novel hepatoprotective therapeutics.