Diterpenoid honatisine overcomes temozolomide resistance in glioblastoma by inducing mitonuclear protein imbalance through disruption of TFAM-mediated mtDNA transcription

•Heptacyclic diterpenoid alkaloid honatisine could be a drug candidate for the treatment of chemoresistant GBM.•Patient-derived GBM organoids was a pragmatic screening model to evaluate antineoplastic activity of lead compounds.•Honatisine induced mitochondrial dysfunction via causing mitonuclear protein imbalance and lethal UPRmt.•Mitochondrial transcription factor A (TFAM) might be a novel target to overcome chemoresistance in GBM.