Antiproliferative effects of pachymic acid on thyroid cancer cells and characterization of its metabolites.

Thyroid cancer (THCA) is the most prevalent endocrine malignancy, underscoring the need for novel therapies. Pachymic acid (PA), a key bioactive triterpenoid from P. cocos, possesses documented anticancer activity, yet its role in thyroid cancer is poorly understood. In this study, we evaluated PA's effects on THCA in vitro and in vivo. Our results revealed that PA potently suppressed THCA cell proliferation, migration and tumor growth. Metabolite profiling identified seven metabolites and their formation pathways. Network pharmacology predicted 147 therapeutic targets, primarily enriched in PI3K-AKT, MAPK, and EGFR signaling, and PA was shown to exhibit the strong and stable binding affinity with AKT, EGFR, HSP90AA1, which was functionally validated by Western blot showing inhibition of AKT (Ser473) and EGFR (Tyr1068) phosphorylation. Crucially, hydrolytic metabolites M4-M7 exhibited superior binding affinity to AKT and EGFR. In summary, PA inhibits thyroid cancer cell proliferation likely through blocking AKT and EGFR signaling, and its hydrolytic metabolites M4-M7 may mediate enhance antitumor activity via more potent target engagement.