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Developing an integrative investigation method of Aconiti kusnezoffii radix.Evaluating the toxicity of Aconiti kusnezoffii radix and the attenuation effect of its processed drug.Verification the nephrotoxicity of Aconiti kusnezoffii radix.Presenting the serum and urine metabolomics.The biomarkers such as Protoporphyrin IX, L-Carnitine, etc. had been found.Aconiti kusnezoffii radix (AKR), the root of Aconitum kusnezoffii Reichb., is commonly used in the treatment of the rheumatoid arthritis. However, the clinical application is limited due to its potential toxicity. Therefore, to investigate the mechanism of its potential neurotoxicity and nephrotoxicity, a comprehensive metabolomics study combined with serum biochemistry and histopathology measurements was carried out. A UHPLC-Q-TOF mass spectrometry based metabolomics approach was applied to characterize the AKR toxicity, while the toxicity attenuation effects of Aconiti kusnezoffii radix cocta (AKRC) on Wistar rats were also investigated. Two chromatographic techniques involving reversed-phase chromatography and hydrophilic interaction chromatography were combined for the serum and urine detection, which balanced the integrity and selectivity of the two matrices. Principal component analysis was used to determine the groups, and principal component analysis discriminant analysis was carried out to confirm the important variables. Then, the developed integrative toxicity evaluation method was applied to assess the toxicity of AKR and the attenuation effect of AKRC. The highly sensitive and specific toxic biomarkers, which can provide practical bases were identified for the diagnosis of the neurotoxicity and nephrotoxicity induced by AKR. In all, a total of 19 putative biomarkers were characterized, and related metabolic pathways were identified. The study demonstrated that the established metabolomics strategy is a powerful approach for investigating the mechanisms of herbal toxicity and the attenuation effect of a processing method and would provide medical solutions for other toxic herbal medications and further clinical evidence on how AKR improves symptoms of rheumatoid arthritis patients.