Sertraline exerted cytotoxic effects in glioblastoma cells by disrupting lysosomal integrity and inhibiting Akt/mTORC1 signalingLysosomal accumulation of sertraline led to membrane permeability, resulting in cell deathPTEN‐intact glioblastomas showed increased sensitivity to sertralineCombination therapy with EGFR or Akt inhibitors enhanced sertraline sensitivity, leading to redox collapseSertraline‐induced cell death was partially rescued by lysosomal function restoration using bafilomycin A1. This evidence concerns the gene EGFR and glioblastoma.