Fig. 3: USP18 promotes resistance by antagonizing sorafenib-induced ferroptosis.

A Scheme displaying the procedure used for identifying biological processes regulated by USP18. B The bubble diagram of KEGG pathway analysis of the top 20 biological processes downregulated by USP18. C CCK-8 assay. USP18 knockdown on the susceptibility to sorafenib in HepG2-SR cells, in the presence or absence of ferroptosis inhibitor (Fer-1, 2 μM) treatment for 24 h (means ± SEM, **p < 0.01 versus siNC, ##p < 0.01 versus siUSP18, paired student’s t-test). D FerroOrange staining. The impact of USP18 overexpression on the sorafenib-induced elevation of Fe2+ levels. Scale bars, 5 μm. E ROS staining. The effect of USP18 overexpression on the generation of ROS induced by sorafenib. Scale bars, 5 μm. F, G BODIPY 581/591 C11 staining (F) and MDA assay (G). The impact of USP18 overexpression on sorafenib-induced lipid peroxidation (means ± SEM, ***p < 0.001, student’s t-test). Scale bars, 5 μm. H Representative transmission electron microscopy (TEM) images of mitochondrial morphological changes in the indicated group. Scale bars, 2 µm (top), 500 nm (bottom).