Fig. 1: URI depletion promotes TKIs-induced ferroptosis in cancer cells.

a Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the differential expressed genes between HepG2-shURI and control cells. The top 24 enriched pathways were listed. The bubble size indicates changed gene numbers and colors represent false discovery rate (P‐value). b Analysis of “WP_Ferroptosis” geneset between HepG2-shURI and control cells by GSEA software (v4.1.0), the NES and FDR P-value were shown. c Relative viability of JHH1 and HepG2 cells treated with different concentrations of sorafenib, lenvatinib, regarofenib, apatinib, erlotinib or donafenib for 48 h and cell viability was assayed by measuring cellular ATP levels (n = 3 biological replicates). d HepG2 cells were treated as indicated for 48 h and cells were then stained with 20 μM C11-BODIPY followed by flow cytometry (n = 3 biological replicates). Sorafenib, (10 μM); lenvatinib, (10 μM); regarofenib (10 μM) for JHH1 cells and (5 μM) for HepG2 cells; apatinib, (20 μM); erlotnib, (20 μM); donafenib, (10 μM). e IC50 values were calculated according to experiments in Supplementary Fig. 2c. f, g, Long-term colony-formation assay of cells treated with or without 2.5 μM sorafenib for 14 days (f), and the quantification of clones were shown in (g) (n = 3 biological replicates). h Cells were treated with or without sorafenib (10 μM) for 24 h and lipid peroxidation was measured (n = 3 biological replicates). i Cells were treated with or without sorafenib (10 μM), antioxidant N-acetylcysteine (NAC, 1000 μM), apoptosis inhibitor Z-VAD-FMK (50 μM), ferroptosis inhibitor ferrostatin-1 (Fer-1, 10 μM), necrosis inhibitor necrostatin-1 (Nec-, 50 μM) or autophagy inhibitor 3-methyladenine (3-MA, 10 μM) as indicated for 48 h, then cell viability was measured (n = 3 biological replicates). Data are means ± SEM. Statistical significance in (c–e) and (g–i) is determined by two-tailed unpaired t-test. Source data are provided as a Source Data file.