Nelfinavir triggers ferroptosis by inducing ER stress mediated downregulation of GPX4/GSH system, upregulation of NRF2/HO-1 axis, and mitochondrial impairment in hepatocellular carcinoma cells.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis. Novel therapeutic strategies for HCC are urgently needed. Ferroptosis, an iron and reactive oxygen species (ROS) dependent regulated cell death, emerges to efficiently abrogate the growth and proliferation of HCC cells. The identification of new ferroptosis inducing agents should provide potential therapeutics for more effective management of HCC. Here we have identified nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor as a novel ferroptosis inducer in HCC cells, Hepa1-6 and HepG2. Mechanistically, the induction of ferroptosis by nelfinavir required its induction of ER stress; suppression of ER stress remarkably attenuated mitochondrial impairment and superoxide production, the aut

SUBMITTER: Zhang L 

PROVIDER: S-EPMC12501057 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature