Fig. 6: LCN2 mediates ferroptosis resistance and is a therapeutic target for enhancing sorafenib efficacy.

a qPCR of Lifr and Lcn2 in Lifr-knockout PHM cells transduced with the scrambled (Scr) or Lcn2 shRNA. n = 3 samples. b Lifr-knockout PHM cells were transduced with Lcn2 shRNA and treated with 10 µM erastin or 20 µM sorafenib. Cell viability was determined by a CCK8 assay. n = 5 wells. c Fe²⁺ levels in liver tissues of Lifr^fl/fl and Lifr^fl/fl;Alb-Cre mice in the absence or presence of hydrodynamic injection of plasmids expressing the Sleeping Beauty transposase, myrAKT, and RasV12. n = 4 mice. d Fe²⁺ levels in control and Lifr-knockout PHM cells transduced with the scrambled (Scr) or Lcn2 shRNA. n = 3 wells. e Malondialdehyde (MDA) levels in control and Lifr-knockout PHM cells transduced with the scrambled (Scr) or Lcn2 shRNA. n = 5 wells. f Glutathione (GSH) levels in control and Lifr-knockout PHM cells transduced with the scrambled (Scr) or Lcn2 shRNA. n = 3 wells. g Immunoblotting of Lifr, Slc7a11, Fsp1, Gpx4, and Gapdh in control and Lifr-knockout PHM cells transduced with the scrambled (Scr) or Lcn2 shRNA. h Immunoblotting of LCN2, LIFR, p-p65, p65, and GAPDH in tumors generated from four PDX lines of HCC. i ELISA of lipocalin 2 in the serum collected from NSG mice bearing PDX line #5. Mice were treated with anti-LCN2 and sorafenib, alone or in combination. n = 7 mice. j, k Growth curves of tumors in NSG mice bearing PDX line #4 (j) or #5 (k). When tumors grew to 50–150 mm³, mice were treated with 100 μg anti-LCN2 and 30 mg kg⁻¹ sorafenib, alone or in combination. The treatments were given 6 days a week for 4 weeks. Statistical significance was determined by a two-way ANOVA. n = 6 mice in j and n = 7 mice in k. l Endpoint tumor images of the mice described in j and k. Statistical significance in b–f and i was determined by a two-tailed unpaired t-test. Error bars are s.e.m. Source data are provided as a Source Data file.