Radix Bupleuri (RB) and acetaminophen (APAP) are two popular medications having potential hepatotoxicity and substantial risks of irrational co-administration and excessive use, posing an overlooked danger of drug-induced liver injury (DILI). Autophagy is a protective mechanism against APAP-induced DILI, yet, saikosaponin d (SSd) in RB has been characterized to regulate autophagy, although the current findings are controversial.

We aim to elucidate whether SSd promoted APAP-induced liver injury by regulating autophagy.

UPLC-MS analysis was employed to measure the hepatic abundance of APAP-cysteine protein adducts. Multiple techniques such as fluorescence probe, proteinase K protection assay, immunoprecipitation-coupled proteomic analysis, surface plasmon resonance, molecular docking and et.al were applied to evaluate the SSd on autophagy flux.

We discovered that, by inhibiting autophagy, SSd impaired the removal of APAP-cysteine protein adducts and delayed the compensation of damaged mitochondria. This ultimately potentiated the development of severe liver toxicity induced by subtoxic APAP. The use of autophagy probes, transmission electron microscopy, membrane curative assay, and protein K assay collectively revealed that SSd predominately disrupted autophagosome-lysosome fusion, without affecting other stages of autophagic flux. Immunoprecipitation-coupled proteomic analysis and surface plasmon resonance further found that SSd directly bound to GABARAP, thus preventing the recruitment and autoactivation of STX17 and the following assembly of STX17-SNAP29-VAMP8 complex.

In conclusion, our findings not only highlight the significant risk of drug-induced liver injury associated with the co-administration of RB and APAP in clinical practice but also unveils that GABARAP-SNARE complex is a novel druggable target for the treatment of autophagy-related diseases.

Polygonum multiflorum Thunb. (PM), a kind of perennial plant, belongs to the genus Polygonum of the family polygonaceae.The dry root of PM (also called Heshouwu), is a traditional Chinese medicine, which has a series of functions and is widely used in clinic for hair lossing, aging, and insomnia. While, PM also has some toxicity, its clinical drug safety has been concerned. In this paper, the chemical components, toxic mechanisms and detoxification strategies of PM were reviewed in order to provide evidence for its clinical application.

We conducted a systematic review of published literature of PM, including English and Chinese databases, such as PubMed, Web of Science, CNKI, and Wanfang.

PM contains a variety of chemical compounds, including stilbenes, quinones, flavonoids, phospholipids, and has many pharmacological activities such as anti-aging, wound healing, antioxidant, and anti-inflammatory properties. The PE has certain therapeutic effect, and it has certain toxicity like hepatotoxicity, nephrotoxicity, and embryotoxicity at the same time, but.these toxic effects could be effectively reduced by processing and compatibility.

It is necessary to further explore the pharmacological and toxicological mechanisms of the main active compounds of PE.This article provides scientific basis for the safe clinical application of PM.

Significance: Herbs are widely used worldwide. However, inappropriate use of some of the herbs can lead to herb-induced liver injury (HILI). Intriguingly, HILI incidents are on the rise, and our understanding of the underlying etiologies is in progress, and hence, an update on the current status of incidents as well as our understanding on the etiologies of HILI is appropriate. Recent Advances: HILI reports due to the use of some herbs that are traditionally considered to be safe are also on the rise. Furthermore, HILI due to the use of certain herbs in combination with other herbs (herb-herb interaction [HHI]) or non-herb components (herb-drug interaction [HDI]) has also been reported, suggesting a potentially important new type of inappropriate use of herbs. Critical Issues: Updated overviews focus on the epidemiology, etiology, phenotypes, and risk factors of HILI, as well as HDI and HHI, and analysis on several types of newly reported "toxic" effects of herbs based on types of hepatotoxicity and the HILI mechanisms. Future Directions: HILI will continue to be a significant public health challenge in the near future. In the light of the lack of broadly available guidelines and regulations for proper and safe uses of herbs worldwide, raising the public awareness of HILI will remain one of the most effective measures. In particular, it should include a better understanding of the contributing factors; a more detail subclassification and description of HILI, better characterization of the components/substances that could induce HILI; and development of HILI diagnosis based on the Roussel Uclaf Causality Assessment Method (RUCAM). Antioxid. Redox Signal. 38, 1138-1149.