Hederagenin exerts anti-tumor effects in pancreatic cancer by impairing DRP1 mediated-mitophagy via VDAC1-HK2-PINK1/PARKIN pathway.

Pancreatic cancer (PC) is widely regarded as the deadliest form of malignancy with a notably bleak prognosis. Although survival rates have shown gradual improvements, the pace of advancement remains slower when compared to other forms of cancer. Mitophagy suppression has surfaced as a novel approach for cancer treatment. Hederagenin (HDG), a triterpenoid extracted from the Hedera helix, has been identified as a potent inhibitor of mitophagy in PC. HDG has demonstrated the capacity to suppress the growth of BXPC-3 and PANC-1 cells in vitro, while also showing efficacy in diminishing tumor expansion in vivo. Furthermore, HDG promoted the opening of mitochondrial permeability transition pores, and enhance the accumulation of ROS. In addition, HDG led to a disruption in autophagic flux and an increase in autophagosomes within PC cells. Western blot analysis suggested that HDG hindered the fusion of lysosomes and autophagosomes by downregulating the expression of SNAP29, LAMP1, and Rab7. HDG also altered mitochondrial morphology in PC cells by suppressing the expression of dynamin-related protein 1 (DRP1), a crucial element in mitochondrial division machinery. This inhibition subsequently triggered voltage-dependent anion-selective channel protein 1 (VDAC1) oligomerization, mitochondrial hexokinase 2 (HK2) dissociation, and downregulation of the PINK1/PARKIN pathway, ultimately inhibiting the proliferation of PC cells in vitro. Moreover, the anti-mitophagy impact of HDG was reversed by DRP1 overexpression, while DRP1 knockdown produced the opposite results. These findings collectively suggest that HDG exerts anti-tumor activity by inhibiting mitophagy in PC cells. The underlying mechanism may involve the suppression of the DRP1-VDAC1-HK2-PINK1/PARKIN signaling pathway.