Donafenib Induces Mitochondrial Dysfunction in Liver Cancer Cells via DRP1.

Abstract

Hepatocellular carcinoma (HCC) represents a significant global health challenge, characterized by a high incidence rate. Mitochondria have emerged as an important therapeutic target for HCC. Donafenib, a multi-receptor tyrosine kinase inhibitor, has been approved for the treatment of advanced HCC. However, the underlying mechanisms remain to be elucidated. In this study, we aim to investigate the effects of Donafenib on mitochondrial function in HCC cells. Firstly, we show that Donafenib induces mitochondrial oxidative stress in SNU-449 liver cancer cells by increasing mitochondrial ROS while reducing glutathione peroxidase (GPx) activity and the expression of Mn-SOD. We also demonstrate that Donafenib decreases mitochondrial membrane potential (MMP) and induces the opening of the mitochondrial permeability transition pore (mPTP). Furthermore, Donafenib reduces mitochondrial respiratory rate, COX IV activity, and ATP production. Notably, Donafenib induces mitochondrial fragmentation and reduces mitochondrial length by increasing the expression of DRP1, without affecting Mfn1 or Mfn2. Silencing of DRP1 protects against mitochondrial dysfunction induced by Donafenib, indicating that DRP1 plays a key role in mediating Donafenib's effects on mitochondrial function in HCC cells.