Comprehensive Review on the Toxicity of Five Main AQ Constituents from Rhubarb: Mechanisms, Challenges and Future Perspectives.

Background: Emodin, rhein, aloe-emodin, physcion, and chrysophanol are five representative anthraquinones (AQs) in rhubarb. They exhibit diverse pharmacological activities, including antitumor, anti-inflammatory, antibacterial, and antioxidant effects, and are widely used in traditional Chinese medicines (TCMs), dietary supplements, and functional foods. However, with their increasing application, the potential toxicity of AQs has become increasingly prominent. Moreover, their toxic mechanisms and metabolism-related toxicities remain incompletely elucidated, which has limited their clinical development and safe application to a certain extent. Objective: This paper systematically reviews the toxicological characteristics, toxic mechanisms, and metabolism-related toxicity of the five major AQs in rhubarb, and explores research strategies for AQs toxicity based on advanced technologies, aiming to provide new insights and references for their safe application and further studies. Methods: A comprehensive search was conducted in PubMed, Google Scholar, Web of Science, and CNKI for peer-reviewed research articles and reviews published in the past 15 years. The research progress of the five major rhubarb AQs and the applications of cutting-edge technologies in their toxicity studies were summarized. Results: The toxicities of AQs mainly target the liver, kidney, heart, reproductive system, and nervous system. Their toxic mechanisms involve multiple pathways, including mitochondrial apoptosis, oxidative stress, death receptor pathway, endoplasmic reticulum (ER)-related apoptosis, caspase-dependent apoptosis, autophagy, inflammation, DNA damage, and bilirubin metabolism. The in vivo metabolism of AQs is complicated, and both Phase I and Phase II metabolites are linked to toxicity. The diverse metabolites can interconvert and undergo various reactions in vivo, posing great challenges for toxicity research. In the future, the application of advanced technologies, such as multi-omics and single-cell sequencing, artificial intelligence (AI) and computer simulation, microfluidics, and mass spectrometry imaging (MSI) will provide strong support for accurately elucidating toxic mechanisms, enabling toxicity prediction, and optimizing detoxification strategies, and will become effective approaches to advance toxicity studies of rhubarb AQs. Conclusion: The intrinsic toxicity and complex metabolic processes of rhubarb AQs restrict their clinical application. Current studies on the toxic mechanisms, metabolism-toxicity relationships, and multifactorial regulation of AQs still require further in-depth investigation. Future research should focus on the metabolism-toxicity relationship, key toxic targets, and detoxification strategies of AQs, and establish an integrated toxicity research system combined with advanced technologies, so as to provide robust support for the safe application and clinical development of rhubarb AQs.