Stiripentol induces ER stress and pyroptosis in pancreatic cancer cells under metabolic stress by dysregulating SFAs/UFAs homeostasis.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by profound chemoresistance, creating an urgent need for novel therapies to overcome treatment failure. Although stiripentol has shown antitumour activity in glioblastoma (GBM), its precise mechanism of action remains unclear. Further investigation is needed to elucidate both its therapeutic efficacy and the underlying molecular mechanisms in PDAC.

Methods: This study validated the proposed mechanisms and therapeutic efficacy through a multi-faceted approach integrating transcriptomic and metabolomic analyses, complemented by both in vivo and in vitro experiments.

Results: CCK8, EdU, and colony formation assays demonstrated that stiripentol inhibited the proliferation of PDAC cells in vitro. PI staining and Western blotting (WB) confirmed that stiripentol induced pyroptosis in PDAC cells cultured under low-serum (1% FBS) condition. Integrated multiomics (RNA-seq and lipid metabolomics), combined with functional validation, revealed that stiripentol triggered endoplasmic reticulum (ER) stress and pyroptosis via SREBP1-SCD/FADS2 pathway-mediated disruption of saturated/unsaturated fatty acids (SFAs/UFAs) homeostasis. Finally, we confirmed that stiripentol synergized with gemcitabine (GEM) to suppress PDAC growth both in vitro and in vivo.

Conclusions: Our findings demonstrate that stiripentol disrupts SFAs/UFAs homeostasis, thereby inducing ER stress and pyroptosis in PDAC cells under serum deprivation condition. Notably, stiripentol has synergistic antitumour effects with GEM, highlighting its translational potential as a promising combination therapy for PDAC treatment.