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This study aimed to investigate whether Xihuang Pills (XHP) enhance the therapeutic efficacy of temozolomide (TMZ) against glioblastoma (GBM) U251 cells by inducing mitochondria-associated ferroptosis via regulation of Nrf2/HO-1/GPX4 signaling axis. The XHP-containing serum was prepared, and the effects of various concentrations of TMZ (0-200 μmol·L-1) and XHP (0-20%) on U251 cell viability were assessed by CCK-8 assay. The optimal synergistic dose (200 μmol·L-1 TMZ + 10% XHP) was identified via the SynergyFinder platform for establishing a combined intervention model. Control, XHP, TMZ, and XHP + TMZ groups were designed. Cell proliferation was evaluated by EdU staining and colony formation assay, and cell migration and invasion were assessed by Transwell and wound healing assays. FerroOrange and DCFH-DA fluorescent probes were used to measure the intracellular levels of Fe2+ and ROS, respectively. The JC-1 fluorescent probe was used to assess mitochondrial membrane potential, while Mito-PeDPP fluorescent probe to examine mitochondrial lipid peroxidation. Mito-Tracker Green and MitoSOXTM Red were used to examine mitochondrial morphology and oxidative stress. Transmission electron microscopy was adopted to observe the mitochondrial ultrastructure. GSH and MDA levels were measured by colorimetric assays. Western blot was employed to assess the protein levels of Nrf2, HO-1, xCT, and GPX4. The results showed that, XHP + TMZ suppressed cell viability, proliferation, migration, and invasion (P<0.01), increased Fe2+ accumulation, ROS generation, GSH depletion, and lipid peroxidation (P<0.001), reduced mitochondrial membrane potential, caused severe structural damage, and down-regulated the protein levels of Nrf2, HO-1, GPX4, and xCT, which indicated that the antioxidant ferroptosis-protective pathway was co-inhibited. In conclusion, XHP enhances TMZ-induced ferroptosis in GBM cells by suppressing the Nrf2/HO-1/GPX4 signaling axis. The findings provide new mechanism insights into the synergistic antitumor effect of traditional Chinese medicine in glioblastoma therapy and offer experimental evidence for the treatment of refractory brain tumors with combined strategies.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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