AimGlioblastoma (GBM), a highly aggressive primary brain tumor, often displays resistance to the standard chemotherapy agent Temozolomide (TMZ), presenting a formidable treatment challenge. This study aims to explore the impact of S100P, a calcium-binding protein linked to TMZ resistance in GBM cells, by investigating the consequences of S100P knockdown on TMZ resistance. The research, employing bioinformatics analysis and siRNA-mediated gene silencing, reveals a significant relationship between S100P and TRIM29 in the context of TMZ resistance. Material and methodsHuman GBM cells underwent transfection with S100P siRNA to achieve targeted suppression of S100P expression. The assessment of TMZ resistance was conducted through MTT cell viability assays, and the molecular mechanisms underlying the observed effects of S100P knockdown on TMZ resistance were explored using real-time PCR. ResultsOur findings reveal a significant reduction in TMZ resistance upon S100P knockdown in GBM cells. This effect is demonstrated by an increase in cell death and a concurrent decrease in the expression of proteins associated with TMZ resistance. ConclusionThe study establishes S100P as a promising therapeutic target to overcome TMZ resistance in GBM. Silencing S100P expression emerges as a strategy to enhance the sensitivity of GBM cells to TMZ chemotherapy. These results advocate further investigations to unveil the clinical viability of targeting S100P in the treatment of GBM.