<p>Temozolomide (TMZ) is the most important chemotherapeutic agent for glioblastoma (GBM), but its clinical efficacy remains limited. Thus, it’s urgent to discover a promising therapeutic target to increase the sensitivity of GBM cells to TMZ. In the present study, real-time PCR, Western blot and IHC analyses demonstrated that TMZ treatment upregulates GDF15 mRNA and protein expression in glioblastoma cells as well as in brain tumors from an intracranial orthotopic GBM mouse model. Overexpression of GDF15 in GBM cells significantly promoted cell proliferation both in vitro and in vivo, whereas knockdown of GDF15 enhanced the anti-tumor activity of TMZ in the orthotopic GBM mouse model. Mechanistic studies using Western blot and IHC analyses revealed that EGR1 expression was increased in GBM cells treated with TMZ; overexpression or knockdown of EGR1 in GBM cells suggested that EGR1 contributes to TMZ-induced GDF15 expression in glioblastoma. Additionally, real-time PCR and Western blot analyses demonstrated that 6-Gingerol, an active ingredient extracted from the plant of ginger, not only suppressed EGR1 and GDF15 expression in GBM cells, but also blocked TMZ-induced the upregulation of GDF15 in vitro and in vivo. Notably, the combination of TMZ and 6-gingerol significantly inhibited tumor growth and prolonged survival in the orthotopic GBM mouse model. Taken together, our study identifies GDF15 as a promising therapeutic target to improve TMZ sensitivity in GBM cells, offering a potential strategy for GBM treatment.</p>