Excessive Use of <i>Polygonatum sibiricum</i> Causes No Acute Lethality but Induces Multiple Toxic Effects in Mice

Polygonatum sibiricum Delar. ex Redoute (P. sibiricum) is a traditional Chinese medicine with multiple health benefits in medicinal-edible dual consumption. However, its toxicological profiles and underlying mechanisms remain poorly characterized, limiting its safe clinical and dietary applications. In this study, an ethanolic extract of P. sibiricum (PS) was obtained via a microwave-assisted ethanol extraction method, and the flavonoid and saponin contents were quantitatively determined via colorimetric assays and high-performance liquid chromatography (HPLC). After oral administration to mouse models, the main blood-accessible constituents, acute, subacute and genetic toxicities, and potential mechanisms were systematically evaluated via HPLC, manifestation observations, routine blood tests, histopathological evaluations, and network toxicology analyses. The results demonstrated that the PS contained 1.138-mg/ml flavonoids and 9.152-mg/ml saponins. Approximately 10 blood-accessible constituents among 15 components were discovered, including diosgenin, 3'-methoxydaidzein, baicalein, (2R)-7-hydroxy-2-(4-hydroxyphenyl) chroman-4-one, 4',5-dihydroxyflavone, (+)-syringaresinol-O-beta-D-glucoside, zhonghualiaoine 1, methylprotodioscin_qt, sibiricoside A_qt and β-sitosterol. Although PS did not cause acute lethality, high-dose exposure induced obvious behavioural changes and chromosomal damage. Subacute administration elicited time-dependent biochemical disturbances and structural lesions in the liver, kidney and spleen. Bioinformatic results linked hepatotoxicity to PI3K-AKT signalling, nephrotoxicity to HIF-1 and MAPK cascades, and splenotoxicity to convergent PI3K-AKT, NF-κB and MAPK pathways. Molecular docking revealed robust interactions between PS constituents and the predicted toxicity-related targets. Taken together, these findings suggest that PS is nonlethal but potentially has genetic and multiorgan toxicities. Multitarget and multipathway mechanisms are involved in PS-induced toxicities. These findings provide a comprehensive toxicological reference for the rational and safe use of P. sibiricum in both medicine and diet.