Capsaicin Enhances Temozolomide-Resistant Glioblastoma Cells’ Chemosensitivity and Ferroptosis through FHOD1/IRF2 Downregulation

Resistance of tumor cells to chemotherapy, particularly in the case of glioblastoma (GBM), a common brain tumor, presents a substantial challenge in oncology. In this study, we investigated the potential of capsaicin to overcome drug resistance in temozolomide (TMZ)-resistant U87 and U251 cells by targeting ferroptosis-mediated interferon regulatory factor (IRF)-2 and formin homology-2 domain-containing protein-1 (FHOD1) signal pathways. First, we induced TMZ resistance in these cells by treating them with TMZ for three weeks. Subsequently, we assessed the impacts of capsaicin on various aspects, including cell viability, proliferation, ferroptosis markers, levels of IRF2 and FHOD1, intracellular iron concentrations, and cell migration in these cells. Our results indicate that capsaicin treatment resulted in a significant decrease in both cell viability and proliferation in TMZ-resistant U87-R and U251-R cells. In addition, it effectively suppressed cell migration rates in these cells, targeting TMZ resistance. Furthermore, capsaicin demonstrated its ability to downregulate FHOD1, IRF2, glutathione, and glutathione peroxidase 4 levels in TMZ-resistant cells. This was accompanied by an increase in intracellular iron, total oxidant status, and increased malondialdehyde levels. Significantly, the treatment with capsaicin led to a notable decrease in the expressions of FHOD1 and IRF2 at both the mRNA and protein levels in U87-R and U251-R cells. In summary, our results emphasize the substantial potential of capsaicin in enhancing the sensitivity of TMZ-resistant GBM cells to chemotherapy. This effect is achieved through its modulation of ferroptosis-related pathways, involving the regulation of FHOD1 and IRF2 expressions.