Abstract: Objective To address the safety concerns about mineral drugs (Cinnabar and Realgar) in Angong Niuhuang Wan (AGNHW) and about the uncertain efficacy of artificial substitutes, and to explore its quality and safety evaluation system in terms of “component interactions within the compound micro-environment”. Methods Recent studies on interactions between “mineral components (toxicity/efficacy)” and “plant/animal components (detoxification/assistance)” in AGNHW were reviewed in general and multidimensional detoxification mechanisms, morphological toxicology, and bioequivalence evaluation in particular. Results There was evidence that AGNHW was not merely a simple mixture of ingredients, but instead a precise “toxicity-regulating system”. Plant and animal components proactively intervened in the in vivo processes of heavy metals via chemical chelation (such as peptides from Bubali Cornu), physiological transport regulation (such as upregulation of P-gp efflux by berberine), and pathological anti-inflammation (such as the antioxidant effect of muscone) so that “toxicity was mitigated while efficacy was retained.” However, current quality control standards failed to cover these critical indicators of “detoxification interactions”. The lack of trace synergistic components in artificial substitutes might compromise this endogenous protective mechanism. Conclusion Research on AGNHW should shift from “quantification of chemical components” to “correlations between interactive mechanisms”. It is recommended that an integrated evaluation system based on “the ability of heavy metals to regulate morphology” and “biological activity fingerprints” be established, and that multi-omics and artificial intelligence be used to elucidate the material basis of the “efficacy-toxicity balance” so as to provide a reference for precise clinical applications of classic formulas.

Key words: Angong Niuhuang Wan, Mineral Drugs, Component Interaction, Compatibility for Toxicity Reduction, Morphology of Heavy Metals, Quality Marker