Multi-omics Reveals Hepatotoxic Mechanisms and Key Toxic Components of Polygoni Multiflori Radix and Its Processed Products

Background Polygoni Multiflori Radix (PMR) and its processed form, Polygoni Multiflori Radix Praeparata (PMRP), are two widely used traditional Chinese medicines (TCM). However, in recent years, frequent reports have emerged regarding their hepatotoxicity. Despite numerous studies, the underlying mechanisms of hepatotoxicity and key toxic components remain poorly understood. Purpose This study aimed to comprehensively elucidate the hepatotoxic processes of PMR and PMRP and identify the principal toxic components. Methods In vivo toxicity tests were carried out to assess the toxicity levels and characteristics of PMR and PMRP. The integration of untargeted serum metabolomics, liver spatial transcriptomics, and liver spatial metabolomics was first employed to elucidate the toxicity mechanisms, which were further validated through metabolite and sensitive index levels and by evaluating protein expression. Mass spectrometry and cytotoxicity tests were utilised to determine the primary toxic components. Results The findings revealed that PMR and PMRP primarily regulate tryptophan metabolism, the tricarboxylic acid (TCA) cycle, purine metabolism, and glutathione metabolism. Furthermore, PMR and PMRP can inhibit the expression of bile acid transporters, causing obstruction of bile acid secretion. These modulations trigger oxidative stress, which subsequently leads to cholestasis. The accumulation of bile acids further intensifies oxidative stress, creating a vicious cycle. Furthermore, emodin was identified as the primary toxic component. Conclusion PMR and PMRP can induce cholestatic liver injury. They exert hepatotoxic effects by establishing a vicious cycle between cholestasis and oxidative stress, with emodin being the key component responsible for this toxicity.