Integrated Chemical Profiling and Toxicological Assessment of Total Polyphenols from Cydonia oblonga Mill. Reveals Potential Safety Concerns Under High-Dose Exposure

The increasing consumption of polyphenol-enriched functional foods and dietary supplements highlights the importance of systematic safety evaluation of these bioactive ingredients under high-dose exposure conditions. This study comprehensively evaluated the toxicological responses associated with total polyphenols from Cydonia oblonga Mill. (TPCOM) and explored their potential biological mechanisms. Ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry identified 89 selected phenolic and related constituents. Acute and 28-day repeated-dose oral toxicity studies were conducted with reference to OECD Guideline 423 and in accordance with OECD Guideline 407, respectively. High-dose TPCOM exposure resulted in dose-associated biochemical and histopathological alterations, with the liver and kidneys identified as major target organs. Integrated systems toxicology approaches, including network toxicology, molecular docking, molecular dynamics simulations, and untargeted plasma metabolomics, revealed potential molecular targets, metabolic disturbances, and candidate biomarkers associated with TPCOM exposure. These findings suggest that excessive intake of TPCOM may be associated with metabolic imbalance, stress-related signaling alterations, and organ injury responses. Further experimental validation is required to confirm the specific molecular pathways involved. This study provides a systematic framework for evaluating the safety of polyphenol-rich functional food ingredients under high-dose exposure conditions.