Toxicology and detoxification processing of Fuzi (Aconitum carmichaelii Debeaux lateral root): a comprehensive review integrating historical perspectives and modern research

Fuzi, the processed lateral root of Aconitum carmichaelii Debeaux (Ranunculaceae), is a vital yet highly toxic botanical drug in traditional Chinese medicine. However, its narrow therapeutic window, driven by highly toxic diester-diterpenoid alkaloids (DDAs), necessitates rigorous processing. Adhering to the four pillars of best practice in ethnopharmacology, this review systematically evaluates the toxic components, multi-organ toxicological mechanisms, and detoxification-oriented processing methods of Fuzi, while critically assessing the scientific quality of modern toxicological studies. Current evidence demonstrates that DDAs exert multi-organ toxicity through voltage-gated sodium channel disruption, mitochondrial dysfunction, and oxidative stress, affecting the heart, liver, kidney, nervous system, and reproductive organs. While traditional processing effectively reduces the toxicity by hydrolyzing DDAs into lower-toxicity metabolites, our critical assessment reveals recurrent methodological limitations in contemporary research. These include the inadequate definition of the botanical material, lack of appropriate controls, and reliance on experimental models with questionable clinical relevance. Despite these flaws, current evidence confirms that inadequately processed Fuzi poses severe cardiotoxic and neurotoxic risks, driving ongoing clinical safety challenges. To bridge traditional practices with modern safety requirements, future research must prioritize rigorous experimental designs, toxicological-endpoint-informed quality standards, and prospective clinical pharmacovigilance.