Fig. 2: Gemcitabine induces ferroptosis and ferroptosis evasion confers gemcitabine resistance.

a Overall survival of patients with PDAC with either high (n = 75 patients, Ferroptosis Low) or low (n = 75 patients, Ferroptosis High) expression of ferroptosis suppressor genes as determined by gene-expression signature (gene list provided in Supplementary Data 3). Log-rank (Mantel–Cox) test. b Relative apoptosis and lipid peroxidation of PANC-1 cells (n = 3 different wells; n = 4 different wells, respectively, one representative experiment of 2 independent experiments is shown) or BxPC3 cells (n = 6 different wells; n = 5 different wells) treated with gemcitabine (GEM) compared to vehicle. c Representative image of gemcitabine-induced apoptosis and lipid ROS after 100 h and 240 h in PANC-1 cells. d Expression of ferroptosis-related genes as measured by RNA-Seq in BxPC3 cells treated for 240 h with vehicle or gemcitabine (n = 4 different wells). e Representative phase contrast image showing PANC-1 cells treated with gemcitabine undergoing cell death. f Oxidized lipid species in PANC-1 cells treated for 240 h with vehicle or gemcitabine (n = 4 different wells). Unpaired two-sided Student’s t-test with Holm–Šídák’s multiple comparisons test. g Time-course confluence of PANC-1 (n = 6 different wells, one representative experiment of 3 independent experiments is shown) or BxPC3 (n = 8; n = 4; n = 2 different wells, respectively, one representative experiment of 3 independent experiments is shown) cells treated with GEM, supplemented with ZVAD or Ferrostatin-1. h MDA abundance in harvested PANC-1 xenografts (n = 5 mice) after one week of treatment with vehicle or gemcitabine (GEM), supplemented with UAMC-3203 or PUFA ePLs. One-way ANOVA with Šídák’s multiple comparisons test. i Survival of PANC-1 xenograft bearing NMRInu/nu mice treated with vehicle (n = 3 mice) or GEM (n = 8 mice), supplemented with the ferroptosis inhibitor UAMC-3203 (n = 10 mice) or PUFA ePLs (n = 10 mice). Log-rank (Mantel–Cox) test. j Tumor volumes of individual PANC-1 xenograft bearing NMRInu/nu mice (n = 10 mice) following treatment with gemcitabine (GEM), supplemented with UAMC-3203. k Tumor volumes of individual PANC-1 xenograft bearing NMRInu/nu nude mice following treatment with gemcitabine (GEM, n = 10 mice) supplemented with PUFA ePLs (n = 11 mice). Error bars represent s.e.m. from mean, but are not depicted when they are shorter than the symbol size. Source data are provided as a Source Data file.