Unveiling the ‘Eating Poison’ of Polygala tenuifolia xylem: Mood changes and myocardial injury

The precise processing methods of traditional Chinese herbal medicines are paramount to ensuring their safety and efficacy. Leigong PaoZhi Lun , the seminal work on the processing of Chinese herbal medicine, documents that the ingestion of Polygala tenuifolia Xylem (PTX) induces a state referred to as "MEN". However, the biological phenotypic effects of PTX-induced "MEN" and its underlying mechanisms remain largely unexplored. This study employs a comprehensive approach, integrating behavioral observations related to the central nervous system (CNS) and cardiovascular system (CVS), electrocardiogram analysis, myocardial enzyme detection, Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS)-based metabolomics, plasma exosomal microRNA (miRNA) sequencing, intracerebral cannulation of the lateral habenula (LHb) with administration of the N-Methyl-D-Aspartate receptor (NMDAR) antagonist 2-amino-5-phosphonopentanoic acid (AP5), molecular docking, and a combination of in silico and wet lab experiments. This multifaceted methodology unveiled the chemical phenotype of PTX, identifying 245 chemical constituents, including 7 specific metabolites. Two key findings emerged: PTX disrupts the glutamate (Glu)-gamma-aminobutyric acid (GABA) balance within the LHb, leading to CNS-related depressive-like mood alterations. Additionally, tenuifolin and sibiricose A5 in PTX mediate aldehyde dehydrogenase 2 (ALDH2) inactivation, resulting in CVS-related myocardial cell damage, subsequently causing increased heart rate and hypoxia. These findings provide a novel research perspective on the "safety" quality control and evaluation of P. tenuifolia . Additionally, they offer new evidence to elucidate the modern scientific implications of the theories of "same origin with different effects" and "co-existence of opposite properties" in traditional Chinese medicine. • PTX disrupts CNS and CVS: causes mood disorders (e.g., depression, anxiety) and cardiovascular damage (e.g., myocardial injury, hypoxia). • Unique compounds: tenuifolin and sibiricose A5 among seven compounds inhibit ALDH2, contributing to myocardial injury. • Biomarkers and targets: miR-122, miR-140, miR-28, miR-326, and miR-590 as biomarkers; NMDAR, GRIA2, DRD2, and ALDH2 as key targets. • TCM support: enhances safety and quality control of Polygala tenuifolia , validating "same origin with different effects" and "co-existence of opposite properties" theories.