[Polyphyllin VII inhibits osteosarcoma xenograft growth in mice by inducing ferroptosis via upregulating SOHLH1].

OBJECTIVES

To investigate the inhibitory effect of polyphyllin VII (PP7) on osteosarcoma xenograft growth in mice and explore the underlying molecular mechanism.

METHODS

Ultra‑performance liquid chromatography‑tandem mass spectrometry was used to analyze the main active components of Paris polyphylla. Six nude mice bearing patient‑derived xenograft (PDX) were randomized into two groups for treatment with 2 mg/kg PP7 gavage or saline every other day for 28 days, and the changes in tumor volume and mass were measured. In cultured 143B and HOS cells, the effect of PP7 treatment (0, 1.25, 2.5, 5, and 10 μmol/L) on cell proliferation was assessed with CCK‑8 assay, and Transwell assays were employed to examine the changes in cell migration and invasion. The target of PP7 was predicted by integrated analyses with single‑cell RNA sequencing (scRNA‑seq), bulk RNA sequencing (bulk RNA‑seq) and molecular docking and verified using Western blotting. In osteosarcoma cells transfected with SOHLH1 siRNAs or a negative control sequence, the effects of PP7 treatment (5 μmol/L) on cell migration, invasion, ferroptosis, reactive oxygen species (ROS) production and lipid peroxidation (LPO) were analyzed.

RESULTS

PP7 was identified as one of the major active constituents of Paris polyphylla. In the tumor-bearing mice, PP7 treatment significantly lower the tumor volume and mass. In 143B and HOS cells, PP7 concentration‑dependently inhibited cell proliferation, and at 5 μmol/L, PP7 significantly inhibited cell proliferation, migration and invasion. Multi‑omics analysis identified SOHLH1 as a potential target of PP7, and Western blotting confirmed that PP7 upregulated SOHLH1 expressions at both the mRNA and protein levels. SOHLH1 silencing obviously attenuated the inhibitory effects of PP7 on cell migration and invasion and reduced PP7‑induced ferroptosis.

CONCLUSIONS

PP7 suppresses osteosarcoma xenograft growth in mice by inducing ferroptosis via upregulating SOHLH1 expression.