Polyphyllin II inhibits thyroid cancer progression by targeting HRH1 and suppressing Wnt/β‑catenin signaling.

Polyphyllin II, a natural steroidal saponin extracted from Paris polyphylla, exhibits potent antitumor activity in thyroid cancer. In the present study, bioinformatics analysis, molecular docking, Drug Affinity Responsive Target Stability assay, Cell Counting Kit‑8 assay, flow cytometry, Transwell assay, wound‑healing assay, reverse transcription‑quantitative PCR, western blotting and xenograft experiments were performed to investigate the antitumor effects and molecular mechanism of polyphyllin II in thyroid cancer. Polyphyllin II significantly inhibited cell proliferation, migration and invasion, while inducing apoptosis more prominently in TPC‑1 cells and causing cell cycle arrest in both TPC‑1 and 8305C cells. By using integrated bioinformatics screening and experimental validation, histamine receptor H1 (HRH1) was identified as a key oncogenic target that is highly expressed in thyroid cancer and contributes to malignant progression. With regard to its mechanism of action, polyphyllin II suppressed HRH1‑mediated activation of the Wnt/β‑catenin signaling pathway, reduced β‑catenin nuclear accumulation and downregulated the expression levels of downstream pathway‑related genes. Collectively, these findings demonstrate that polyphyllin II attenuates thyroid cancer progression by targeting HRH1 and blocking Wnt/β‑catenin signaling, highlighting its potential as a promising candidate for targeted therapy.