Oridonin induces ferroptosis by inhibiting ubiquitin-mediated degradation of HMOX1 in hepatocellular carcinoma.

Oridonin is a diterpene compound extracted from Rabdosia rubescens. Although it has been shown to have anticancer effects on several cancers, including hepatocellular carcinoma (HCC), the mechanism remains unclear. HepG2 cells were treated with different concentrations of oridonin for 48 h. Cell viability was detected by CCK-8 assay. The Fe2+ level was detected by iron assay kit. Flow cytometry was used to quantify the lipid reactive oxygen species. The protein and mRNA levels were detected by Western blot and quantitative real-time polymerase chain reaction. The anti-HCC mechanism of oridonin in vivo was investigated using a xenograft tumor model. To explore the underlying mechanisms, bioinformatics methods, immunoprecipitation, and molecular docking were applied. Oridonin inhibited cell viability and induced oxidative stress and ferroptosis. Oridonin also suppressed tumor growth via the ferroptosis-related mechanism. HMOX1 was found to be an interacting protein of oridonin, and oridonin induced ferroptosis by targeting HMOX1. In addition, oridonin promoted the stability of the HMOX1 protein by suppressing its ubiquitination at the K86 site. This study demonstrated that oridonin may inhibit tumor growth via ferroptosis through the inhibition of the HMOX1 ubiquitination process. The study findings will provide new therapeutic targets for HCC.